TW201217392A - Substituted nucleotide analogs - Google Patents

Abstract

Disclosed herein are phosphorothioate nucleotide analogs, methods of synthesizing phosphorothioate nucleotide analogs and methods of treating diseases and/or conditions such as viral infections, cancer, and/or parasitic diseases with the phosphorothioate nucleotide analogs.

Description

201217392 VI. Description of the invention: [Technical field to which the invention pertains] This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, the present invention discloses a thioglycolate nucleoside analog, including a pharmaceutical composition of geisha, a nucleotide analog, and a method of synthesizing the same. Also disclosed herein are methods of treating a disease and/or condition with a phosphorothioate nucleotide analog alone or in combination with other agents. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the US Provisional Application No. 61/385,363, filed on Sep. 22, 2010. Both are incorporated herein by reference in their entirety, in their entirety. [Prior Art] Nucleoside analogs are compounds which have been shown to exert antiviral and anticancer activities in vitro and in vivo, and thus have been extensively studied for the treatment of viral infections and cancer. Nucleoside analogs are generally non-therapeutic active compounds which are converted by the host or viral enzyme into their respective active antimetabolites which in turn inhibit the polymerase involved in viral or cell proliferation. Activation can be accomplished by multiple mechanisms, such as the addition of one or more phosphate groups and other metabolic processes. or in combination with other metabolic processes. SUMMARY OF THE INVENTION Some embodiments disclosed herein are directed to a compound of formula (1) or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a neoplastic disorder 158865.doc 201217392, which can comprise administering to a subject having a neoplastic disorder a therapeutically effective amount of one or more compounds of formula (I), or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising - or a plurality of compounds of the formula (1) or a pharmaceutically acceptable salt thereof. Other embodiments described herein are directed to the use of one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for ameliorating and/or treating a neoplastic disorder. Other embodiments described herein pertain to a compound of formula (1), or a pharmaceutically acceptable salt thereof, useful for ameliorating and/or treating a neoplastic disorder. Some embodiments disclosed herein are directed to methods of inhibiting tumor growth, which can comprise administering to a subject having a tumor a therapeutically effective amount of one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof, & one or more A pharmaceutical composition of a compound of formula (1) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting tumor growth. Other embodiments described herein pertain to one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof useful for inhibiting tumor growth. Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a viral infection, which can comprise administering to a subject having a viral infection a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable compound thereof A salt, or a pharmaceutical composition comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for ameliorating and/or treating a viral infection. Other embodiments described herein pertain to salts which are useful for ameliorating and/or treating a viral infection, one or more compounds of formula (1), or a pharmaceutically acceptable I58865.doc -4- 201217392. Some embodiments disclosed herein are directed to methods for ameliorating and/or treating viral infections, which may include administering a virus-infected cell with an effective amount of one or more of the compounds described herein, or - or a plurality of compounds described herein. An acceptable salt, 4 is contacted with a pharmaceutical composition comprising one or more compounds described herein or a therapeutically acceptable salt thereof. Other embodiments described herein are directed to the use of a compound described herein, or - or a plurality of pharmaceutically acceptable salts of the compounds described herein, to manufacture a medicament for ameliorating and/or treating a viral infection, the improvement And/or treating a viral infection can comprise contacting the virus-infected cell with an effective amount of the compound or compounds. Other embodiments described herein pertain to pharmaceutically acceptable salts, amelioration and/or treatment, for use in ameliorating and/or treating a viral infection, one or more of the compounds described herein, or one or more compounds described herein. Viral infection is achieved by contacting the virus-infected cells with an effective amount of the compound or compounds.

V Some embodiments disclosed herein are directed to methods of inhibiting viral replication, which can include sensitizing a virus-infecting cell with an effective amount of one or more compounds described herein, or one or more compounds described herein. A salt, or a pharmaceutical composition comprising one or more compounds described herein, or a pharmaceutically acceptable salt thereof, is contacted. Other embodiments described herein are directed to the use of one or more compounds described herein, or one or more pharmaceutically acceptable salts of the compounds described herein, to produce a medicament for inhibiting viral replication, which may include The virus-infected cells are contacted with an effective amount of the compound or compounds. Other embodiments described herein pertain to pharmaceutically acceptable salts of one or more of the compounds described herein, or one or more compounds described herein, which are useful for replication of a virus, 158865.doc 201217392, which inhibits viral replication. This is achieved by contacting the virus-infected cells with an effective amount of the compound or compounds. Some embodiments of the invention, a method for improving I or treating a parasitic disease, which may comprise administering to a subject having a parasitic disease a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable thereof An acceptable salt, or a pharmaceutical composition comprising - or a plurality of compounds of formula (1) or a pharmaceutically acceptable salt thereof. Other embodiments described herein are directed to the use of one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for ameliorating and/or treating a conidious disease. Other embodiments described herein pertain to one or more compounds of formula (1), or a pharmaceutically acceptable salt thereof, useful for ameliorating and/or treating parasitic diseases. Some embodiments disclosed herein are directed to methods of ameliorating and/or treating a viral infection, which can comprise administering to a subject having a viral infection a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof (eg, one or a plurality of compounds of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, and an agent selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV Polymerase inhibitor, NS5A inhibitor, other antiviral compound; formula (AA) character of its mono-acid ester, dibasic acid vinegar and / or tridecanoate or a pharmaceutically acceptable salt thereof; A compound or a pharmaceutically acceptable salt thereof, and a compound of the formula (DD) or a pharmaceutically acceptable salt thereof. Disclosed herein is a method for ameliorating and/or treating a viral infection, comprising 158865.doc 201217392 infected with a virus and a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable compound thereof Accepted salts (for example one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound described herein, and a pharmaceutical agent selected from the group consisting of interferon, ribavirin, HCV egg' white enzyme inhibitor, HCV polymerase inhibitor, NS5 A inhibitor, other anti-viral compounds; compounds of formula (AA), monophosphates, diphosphates and/or triphosphates or their medicinal An acceptable salt; a compound of the formula (BB) or a pharmaceutically acceptable salt thereof, and a compound of the formula (DD) or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein are directed to methods of inhibiting viral replication, which can comprise administering to a subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof (eg, a compound of formula (I) or a pharmaceutically acceptable compound thereof Accepted salts), or pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and an agent selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A Inhibitor, other antiviral compound; a compound of formula (AA), a monophosphate, a diphosphate thereof and/or a triphosphate or a pharmaceutically acceptable salt thereof; a compound of formula (BB) or a pharmaceutically acceptable compound thereof a salt thereof, and a compound of the formula (DD) or a pharmaceutically acceptable salt thereof. In some embodiments, the agent may be a compound selected from the group consisting of the compounds 1001-1014, 2001-2010, 3001-3008, 4001-4005, > 5001-5002, 7000-7077, 8000-8012 or 9000 or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more of the above compounds or a pharmaceutically acceptable salt thereof. In some embodiments, the method can comprise administering a second agent selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5 A inhibitor, other 158865.doc 201217392 antiviral compound a compound of the formula (AA), a monophosphate thereof, a bisphosphonate and/or a triphosphate or a pharmaceutically acceptable salt thereof; a compound of the formula (BB) or a pharmaceutically acceptable salt thereof and a formula ( DD) a compound or a pharmaceutically acceptable salt thereof. In some embodiments, the viral infection is HCV. [Embodiment] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by the ordinary skill. All patents, applications, published applications, and other publications, which are hereby incorporated by reference in their entirety herein in their entirety herein in In the case where there are a plurality of definitions of the terms herein, unless otherwise stated, the definitions in this section are dominant. Any "R" group as used herein, such as (not limited to) R, r1, R2, Rh, ..., r4, r5, r6, r7 r8 r9 r丨. r丨丨R丨2, R丨3, R14, Ri5 R1a, R2a, r

3A

R

3B

R16 R4A R丨 7, R18, r19, r20, r21, R5A, R6A, R7A, R8A, r9A and R are not attached to the substituents of the indicated atoms. The R group may be substituted or substituted. If two "R" groups are described as "connected", the 4 R group and the atom to which it is attached may form a cycloalkyl, aryl, heteroaryl group: heterocycle: for example (not Limited to), if Rla and R]b of the NRlaRlb group are linked to each other, it means that they are covalently bonded to each other to form a ring.

When the group is expected to be "optionally substituted", the group may be substituted by one or more of the substituents shown in 158865.doc 201217392. Likewise, when a group is described as being unsubstituted or substituted, the substituent may be selected from one or more of the substituents indicated, if substituted. If a substituent is not indicated, it is meant that the "optionally substituted" or "substituted" group as indicated may be substituted by one or more groups individually and independently selected from alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, thiol, protected Hydroxy, alkoxy, aryloxy, sulfhydryl, decyl, alkylthio, arylthio, cyano, halogen, thiocarbonyl, hydrazine-amine, hydrazino, hydrazine Aminomethyl thiol, N-thioaminyl, c-nonylamino, N-decylamine, s-sulfonylamino, N-sulfonylamino, c-carboxy, protected c-carboxyl , 〇 carboxy group, isocyanate group, thiocyano group, isothiocyanato group, nitro group, decyl group, sulfenyl group, sulfinyl group, sulfonyl group, dentate group, dentate group, tri-methane sulfonate Sulfhydryl, tridentate methanesulfonylamino, amine, monosubstituted amine groups and disubstituted amine groups, and protected derivatives thereof. As used herein, "(^ to 仏" (where "a" and rb" are integers) refers to the number of carbon atoms in the alkyl, alkenyl or alkynyl group, or cycloalkyl, cycloalkenyl, cycloalkynyl, aryl The number of carbon atoms in the ring of a heteroaryl group or a heteroalicyclic group, that is, a ring, an alkenyl group, a block group, a ring of a cycloalkyl group, a ring of a cycloalkyl group, a ring of a ring fast group, and an aryl group. The ring of a ring, a heteroaryl ring or a heteroalicyclic ring may contain "a" to "b" (including "a" and "b") carbon atoms. Thus, for example, "Ci to C4 alkyl" Means all of the yards having 1 to 4 carbons, namely ch3_, CH3CH2-, ch3ch2ch2-, (CH3)2CH-, ch3ch2ch2ch2-, CH3CH2CH(CH3)- and (CHAC-. For alkyl, alkenyl, alkyne Base, 158865.doc -9- 201217392 Cycloalkyl, cycloalkenyl, oxime I., w - "nonynyl, hydroxy, heteroaryl or heteroalicyclic" and b" The broadest range recited in these definitions. As used herein, "alkyl" refers to a straight or branched bond hydrocarbon chain 1 group containing a fully saturated (no double or parametric bond) k group. 2 碳 a carbon atom (when f is in this article At present, such as "a range of values from 1 to" refers to a volume in a given range, and each integer, such as "1 to 2 carbon atoms" means that the alkyl group may be one carbon atom, two carbon atoms, three carbon atoms. The composition of up to 20 carbon atoms (and including 20 carbon atoms), although the definition of the invention also covers the occurrence of the term "hospital" in the unspecified range of values. The yard may also have from [...] one to one carbon atom. The medium group may be a lower alkyl group having (1) carbon atoms. The alkyl group of the compound may be designated as "CiC4 alkyl group" or the like. By way of example only, "Ci_C4 alkyl group" indicates a burning group. There are 1 to 4 carbon atoms in the bond', that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl and t-butyl groups. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted. As used herein, "alkenyl" refers to a nominee having one or more double bonds in a direct or branched bond hydrocarbon bond. Substituted or substituted. As used herein, "alkynyl" refers to a court group containing one or more reference bonds in a straight or branched hydrocarbon chain. Alkynyl groups may be unsubstituted or substituted. "Circular base" means a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (without double bonds or referenced bonds). When composed of two or more rings, the rings may be joined together in a slightly connected manner. The cycloalkyl group may contain 158865.doc •10·201217392 having 3 to 10 atoms or 3 to 8 atoms in the ring. The cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include ( However, it is by no means limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. As used herein, t "ring dilute" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more than one double bond in at least one ring; in the presence of more than one double 1 Μ, the double bond cannot A completely delocalized electronic system is formed throughout all of the rings (otherwise the group is an "aryl" as defined herein). When composed of two or more rings, the rings may be joined together in a fused manner. The cycloalkenyl group may be unsubstituted or substituted. As used herein, "cycloalkynyl" refers to a monocyclic or polycyclic smog system containing one or more reference bonds in at least one ring. If more than one parameter is present, the parameter cannot form a fully delocalized redundant electronic system in all of the rings. When composed of two or more rings, the rings may be joined together in a slightly combined manner. The cycloalkynyl group may be unsubstituted or substituted. As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including a fused ring system in which two carbon rings share a chemical bond), which is completely delocalized throughout all rings. After that, the electronic system. The number of carbon atoms in the aryl group can be: the same. For example, the aryl group can be a C6_Cm aryl group, a Μα aryl group or a aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and chamomile rings. The aryl group may be substituted or unsubstituted. As used herein, a heterocyclic ring system containing one or more heteroatoms (ie, elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) (with complete delocalization) The ring system of the π electronic system). The number of atoms in the ring of the heteroaryl group may vary. For example, a heteroaryl group can contain 158,865.doc 201217392 4 to 14 atoms in the ring and contain 5 to 1 G original atoms in the ring. In addition, the torsion "application pen 1 3 contains 5 to 6 in the ring. The heterosexual storm" includes a thick antic ring (such as at least one aromatic ring and at least one hetero system, two of which are shared) at least one Chemical bond.杂 杂 ζ 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或Azole, oxime 24 < also ox, oxazole, benzo, oxadiazole, thiazole, cold a saliva, 1 2 4-read-ground 1'2, 3 - sold a 5 5 this ° sitting, D rice saliva Stupid and slaughtered, bowed beer, ten sitting. Compared with saliva, benzo D, saliva, isosazole, benzotriazine, thiadipine, (iv) sinister saliva, isothiazol, oxime, qin, (four)... than Qin, sputum, acridine, quinoline, Different saliva, a - 〇* Μ ^ Lin, quinolin, broken Lin and two Qin. The heteroaryl group may be substituted or unsubstituted. As used herein, "heterocyclic group or "" and heterozygous ring base" means 3 members, 4 members, 5 members, 6 members, 7 members, 8 members, 9 members, 1 () members up to 18 members of the single ring. The bicyclic and tricyclic systems in which the carbon atom together with 1 to 5 heteroatoms form the ring system. The heterocycle may optionally contain one or more unsaturated bonds, however, the - or more unsaturated bonds are disposed in such a manner that there is no fully delocalized pi-electron system throughout all of the rings. Heteroatoms are elements other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. The heterocyclic ring may further contain one or more substituents or thiol groups such that the definition includes oxo systems ((10), etc. (4) and thio-systems such as decylamine, lactone, ring An imine, a cyclic thioimine, and a cyclic urethane. When composed of two or more rings, the rings may be fused together. In addition, the heteroalicyclic group Any of the nitrogens may be quaternized. The heterocyclyl or heteroalicyclic group may be unsubstituted or substituted. The "heterocyclyl" or "heteroalicyclic" is 158865.doc -12- 201217392 Examples include, but are not limited to, 1,3·dioxacyclohexene, anthracene, 3-dioxane, anthracene, 4-dioxane, 1,2-dioxolane, and dioxin. Pentane, dioxanthene, 1,1,3, oxosulfonate, oxime-oxo-tung, 1,3-oxathiolane, 1,3-dithiol, 1,3-disulfide Heterocyclic pentane, anthracene oxysulfonium, tetrahydro-indole-thiazine, 2Η-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobar Bis-acid, di-side oxypiperazine, beta-ureaurea, dihydrouracil, dioxane, six _ 1,3,5_triazine, imidazoline, imidazolidinium, isoxazole, iso- ° ° sit bite, ° 唾 琳 、 。 。 。 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 嗤, sales ° Gui bite, 淋 、, epoxy B from, β bottom bite ^ _ oxide, β bottom sediment, D bottom 嗓, 〇 than 0 each bite, " Billo bite, η 洛 烧〇lidi〇ne), 4_ 咬 bottom biting ketone, 吼0 sitting lin, ° than saliva bite, 2-sided oxy η than 唆 唆, tetrahydro mai β south, 4 Η- π bottom taste, tetrahydrothio urethane, Thiomorpholine, thiomorpholine sulfoxide, thiomorpholinium, and benzene fused analogs thereof (eg, benzopyrrolidone, tetrahydrogenin, 3,4-methylenedioxy) Phenyl). As used herein, "aralkyl" and "aryl" refer to an aryl group attached as a substituent via a lower alkyl group. The lower alkyl group of the aralkyl group and the aryl group The group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl. "Heteroaralkyl" as used herein and "Heteroaryl (alkyl)" refers to a heteroaryl group attached as a substituent via a lower alkyl group. The lower alkylalkyl and heteroaryl groups of the heteroarylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl , thiophenealkyl, fluorenylalkyl, acridinylalkyl, isoxazolylalkyl and imidazolylalkyl and benzene fused analogs thereof 158865.doc •13- 201217392 (heteroalicyclic) "Alkyl" and "(heterocyclyl)alkyl" mean a heterocyclic or heteroalicyclic group attached as a substituent via a lower alkylalkyl group. (heteroalicyclic) alkyl lower alkyl And the heterocyclic group may be substituted or unsubstituted. Examples include, but are not limited to, (tetrahydro-2H-piperidin-4-yl)indenyl, (piperidin-4-yl)ethyl, (piperidine- 4-yl)propyl, (tetrahydro-2H-thiothiopyran-4-yl)indenyl and (1,3-thiazinyl-4-yl)methyl. The "low carbon number alkyl group" is a linear _Ch2_ tethering group which forms a bond to link a molecular fragment via its terminal carbon atom. Examples include, but are not limited to, methylene (_CH2_), ethyl (_CH2CH2), propyl (-ch2ch2ch2-) and butyl (_CH2CH2CH2CH2). The lower carbon alkyl group may be substituted by substituting one or more hydrogens of the low * anisotropic extension group by the substituents listed under the definition of "substituted". As used herein, "alkoxy" refers to the formula _〇R' wherein the ruthenium is alkyl, county, alkynyl, cyclo (tetra), cycloaliphatic or cycloalkynyl as defined above. A non-limiting list of alkoxy groups is foxy, ethoxy, n-propoxy, _methylethoxy (isopropoxy), n-butoxy, isobutoxy, second butoxy Base and third butoxy group. The alkoxy group may be substituted or unsubstituted. As used herein, "mercapto" refers to a hydrocarbyl, fluorenyl, alkynyl or aryl group attached as a substituent via (iv). Examples include methyl, ethyl, propyl, benzoyl and (iv) fluorenyl. The brewing base can be substituted or unsubstituted. + "(四)基", as used herein, means that - or a plurality of hydrogen atoms are replaced by a transradical group. (IV) The 1 (4) group includes, but is not limited to, 2_ethyl, 3-propylpropyl, 2-hydroxypropyl. Base and 2,2-dihydroxyethyl. The hydroxyalkyl group may be substituted or 158865.doc -14-201217392 unsubstituted. As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (eg, mono-, di-, and tri-alkyl groups including, but not limited to, chlorine). Methyl, fluoromethyl, difluoromethyl, tris-methyl and 1-oxa-2-fluoroindenyl, 2-fluoroisobutylalkyl may be substituted or unsubstituted. "Alkoxy" means an alkoxy group (eg, monodentate alkoxy, dentate alkoxy, and trihaloalkoxy) wherein one or more hydrogen atoms are replaced by a halogen. These groups include, but are not limited to, chlorine. Methoxy, fluoromethoxy, dimethoxycarbonyl, trifluoromethoxy and 1-oxa-2-fluorodecyloxy, 2-fluoroisobutoxy. Haloalkoxy may be substituted or not As used herein, "aryloxy" and "arylthio" refer to R〇_ and Rs_ where R is aryl, such as, but not limited to, phenyl. Both aryloxy and arylthio groups may be used. Substituted or unsubstituted. "Sulfosyl" means a radical "_SR" wherein r can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, Heteroaryl, heteroalicyclic, aralkyl or A heteroalicyclic)alkyloxasulfonyl group may be substituted or unsubstituted. A (tetra)indenyl group refers to a "_S(=0)-R" group, wherein r may be the same as defined for a sulfenyl group. The sulfinyl group may be substituted or unsubstituted. "Sulfo" refers to a "SOjR" group, wherein r may be the same as defined for sulfenyl. The sulfonyl group may be substituted or unsubstituted. 0-stable group means "RC(= 〇)〇_" group where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyne 158865 as defined herein .doc •15- 201217392 aryl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. 〇-carboxy may be substituted or unsubstituted β

The terms "ester" and "c.carboxy" refer to a "_C(=0)0R" group, wherein R may be as defined for Ο-carboxy. The ester and C-carboxy group may be substituted or unsubstituted. "Thiocarbonyl" means a "-C(=S)R" group, wherein the ruthenium may be the same as the 〇-carboxyl group. The thiol group may be substituted or unsubstituted. "Trihalomethanesulfonyl" refers to the "X3CS02_" group, which is also a halogen. "Dihalosulfonylsulfonylamino" means a group of r X3CS(〇)2N(Ra)_", wherein X is halogen and the ruler is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, ring Alkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. The term "amino" as used herein refers to a _NH2 group. The term "hydroxy" as used herein refers to a 〇H group. "Cyano" means a "-CN" group. The term "azido" as used herein refers to a _n3 group. "Isocyanate group" means a "_NC〇" group. "Thiocyano" means a "_CNS" group. "Isothiocyanato" means "_NCS" group" "酼基" means "_SH" group. "Carbon j refers to a C=fluorene group. "S-sulfonylamino" refers to a "_s〇2N(RaRb)" group in which Rb is independently hydrogen, alkyl, alkenyl 'alkynyl , cycloalkyl, cycloalkenyl, 158865.doc -16 · 201217392 cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic) alkyl. The s-indolyl group may be substituted or unsubstituted. "N-sulfonylamino" means a "RS〇2N(Ra)_" group wherein R and Ra are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or ring. Alkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. The N-anthracene amino group may be substituted or unsubstituted. "0-Amine-based" means a group of "_〇C(=〇)n(RaRb)", wherein RA and RB are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, ring Alkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic) alkyl. The 0-aminoindolyl group may be substituted or unsubstituted. "N-Amine thiol" means a group of "r〇c(=〇)n(Ra)_", wherein R and Ra are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. The N-amine carbenyl group may be substituted or unsubstituted. "〇-Thiocarbamimidyl" means a group of "_〇c(=s)_n(RaRb)", wherein RA and RB are independently hydrogen, alkyl, alkenyl, alkynyl, cyclyl 'Cycloalkenyl'cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic) alkyl. The hydrazine-thioamine thiol group may be substituted or unsubstituted. "N-Thioaminyl" means a group of "r〇c(=s)n(Ra)_" wherein R and RA are independently hydrogen, alkyl, dilute, alkynyl, cycloalkyl Cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. The N-thioaminecarbamyl group may be substituted or unsubstituted. "C-Amino" refers to a "_c(=〇)N(RARB)" group, wherein the octagonal and RB are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl 158865.doc •17· 201217392 Cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic) fen. The c-guanidino group may be substituted or unsubstituted. "N-Amidino" means a group of "rc(=〇)n(Ra)_", wherein the ruler and the ruler are independently argon, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl Alkyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl or (heteroalicyclic)alkyl. The N-guanidinyl group may be substituted or unsubstituted. The term "halogen atom" or "halogen" as used herein means any of the radiation stability atoms of row 7 of the Periodic Table of the Elements, such as fluorine, gas, bromine and iodine. In the case where the number of substituents (e.g., adentate alkyl group) is not illustrated, one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different elements. As another example, "Ci_C3 alkoxyphenyl" may include one or more alkoxy groups which may be the same or different containing one, two or three atoms. Unless otherwise indicated, any protecting group, amino acid, and other compounds as used herein are used in accordance with their common usage, recognized abbreviations, or the IUPAC-IUB Biochemical Nomenclature Commission (c〇mmissi〇n 〇n)

Biochemical Nomenclature) (see Biochem 11:942-944 (1972)) The term "nucleoside" is used herein in its ordinary meaning as understood by those skilled in the art and refers to linkage via a glycosidic linkage. To a heterocyclic base or a tautomer thereof, such as via a substituted pentose moiety or a modified pentose moiety, via a hydrazine, a 9-position of a test group or a 1-position of a bite test. Compound. Examples include, but are not limited to, ribose containing a ribose moiety 158365.doc • 18· 201217392 Nuclear bitterness and deoxyribose nuclear bitter containing the deoxyribose moiety. The modified pentose sugar is divided into a pentose p-cutting nucleus in which an oxygen atom is replaced by carbon and/or carbon is replaced by a sulfur or an oxygen atom, and the monomer having a substituted substituent and/or a sugar moiety may be additionally used. Incorporation into large DNA and / or rna polymers and oligomers. In some cases, the nuclear nucleus may be a nuclear drug. ^ As used herein, the term "heterocyclic test" refers to a pentose moiety or a modified pentose moiety that can be attached to an optionally substituted pentose moiety. A nitrogen-containing hetero group substituted as appropriate. In some embodiments, the heterocyclic test group may be selected from optionally substituted purine bases, optionally substituted pyrimidine bases, and optionally substituted triazole bases (eg, liminazole) "嘌呤 base" is used herein in its ordinary meaning as understood by those skilled in the art, and includes its tautomers. Similarly, the term "bite test" is used herein as if The general meaning of this technology is understood by the skilled artisan and includes its tautomers. A non-limiting list of optionally substituted purine bases including purines, adenines, guanines, hypoxanthine, yellow嗓呤, 嗓呤黄嗓呤, 7_ alkyl guanine (such as 7_ guanine guanine), cocoaline, caffeine, uric acid and isoguanine. Examples of pyrimidine bases include (but are not limited to) cytosine, chest Pyrimidine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (eg 5-methylcytosine). Examples of optionally substituted triazole bases are hydrazine, 2,4•triazole -3-decylamine. Other non-limiting examples of heterocyclic bases include diamino guanidine, 8-sided oxygen -N6-alkyl adenine (eg 8_sideoxy_N6_methyl adenine), 7-diazonium xanthine, 7-deazaguanine, 7-deaza adenine, n4'n4-vinyl Cytosine, N6, N6_Ethylene-2,6-diaminopurine, 5-halouracil (eg 5-fluorouracil and 5-bromouracil), pseudoisomeromide, iso-158865.doc •19_ 201217392 Other heterocyclic bases as described in U.S. Patent Nos. 5,432,272 and 7,125,855, the disclosures of each of which are hereby incorporated herein by In some embodiments, a heterocyclic base may be optionally substituted with an amine or enol protecting group. The term "N-linked amino acid" refers to an amine group attached to the indicated moiety via a backbone amino group or a monosubstituted amine group. Acid. When the amino acid is attached as an N-linked amino acid, one hydrogen belonging to the main chain amine group or the monosubstituted amine group is not present and the amino acid is linked via nitrogen. The term "amino acid" as used herein. "" means any amino acid (standard amino acid and non-standard amino acid) including, but not limited to, CX-amino acid, β-amino group , γ-amino acid and §_amino acid. Examples of suitable amino acids include, but are not limited to, alanine, aspartic acid, aspartic acid, cysteine, glutamic acid, bran Aminic acid, glycine, valine, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, sulphamine Acids, tryptophan acids and valine acids. Other examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, γ-Aminobutyric acid, citrulline, β-alanine, α-ethyl-glycine, α-propyl-glycine and orthraenic acid. The hydrazine-linked amino acid may be substituted or not The term "anthracene-linked amino acid ester derivative" means an amino acid in which a main chain carboxylic acid group has been converted into an ester group. In some embodiments, the ester group has a formula selected from the group consisting of alkyl-0-C(=〇)-, cycloalkyl-〇_c(=〇)_, aryl_〇c(=〇)_ And aryl (alkyl)-0-C(=0)-. A non-limiting list of ester groups includes methyl-0-C(=0)-, ethyl_〇_c(=〇)-, n-propyl_〇_c(=0)_, isopropyl-oxime -C(=0)-, n-butyl_0_c(=0)_, isobutyl-〇c(=〇), third butyl 158865.doc •20· 201217392 base-0-C(=0)- , neopentyl_0_c(=0)_, cyclopropyl-〇c(=〇), cyclobutyl-0-C(=0)-, cyclopentyl_〇_c(=〇)_ ' ring Hexyl-〇c(=〇), phenyl-OC(-O)-', and benzyl_〇_c(=〇)_. The N-linked amino acid ester derivative may be substituted or unsubstituted. As used herein, the term "protecting group" refers to any atom or group of atoms added to a molecule to prevent unwanted groups from undergoing unwanted chemical reactions in the group. Examples of protecting group moieties are described in w Greene & p G M Us, Pr〇tective Groups in 〇rganic - a, 3rd edition,

John Wiley & Sons, 1999 and J.F.W. McOmie, /V valent ve k c/zemWo; Plenum Press, 1973, both of which are incorporated herein by reference for their limited purpose to disclose suitable protecting groups. The protecting group moiety can be selected in such a way that it is stable to certain reaction conditions and is readily removed at the appropriate stage using methods known from the art. A non-limiting list of protecting groups includes benzyl; substituted benzyl, alkyl carbonyl and alkoxycarbonyl (eg, tert-butoxycarbonyl (B〇c), ethionyl or isobutyl); aryl Alkylcarbonyl and arylalkoxycarbonyl (e.g., phenoxymethyl); substituted oxime ether (e.g., methoxy oxime ether); substituted diethyl ether; substituted benzyl ether; tetrahydroperiline a decyl ether; a decyl group (eg, trimethyl decyl, triethyl decyl, triisopropyl decyl, tert-butyl dimethyl decyl, triisopropyl decyloxymethyl, [2- (trimethyldecyl)ethoxy]methyl or tert-butyldiphenylsulfanyl); ester (eg benzoic acid vinegar); carbonate (eg decyloxymethyl carbonate); sulfonate ( For example, a sulphuric acid vinegar or mesylate; an acyclic ketal (such as dimethyl acetal); a cyclic condensate (such as 1,3-dioxane, 1,3-dioxolane) And as described herein; acyclic 158865.doc -21 - 201217392 acid; cyclic acetal (such as described herein); acyclic hemiacetal; cyclic hemi-acid, ring two a thioketal (e.g., 1,3,2 (tau or 1,3-dithiolane); an orthoester (such as described herein) and a triarylmethyl group (e.g., trityl; Monodecyloxytriphenyl fluorenyl (MMTr); 4,4'-dimethoxytrityl (DMT〇; 4,4',4"-trimethoxytrityl (TMTr); As used herein, "leaving group" refers to any atom or moiety that is capable of being replaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, "leaving group" Refers to an atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, a "leaving group" is any atom or moiety that is a conjugate base of a strong acid. Examples of suitable leaving groups include, but are not limited to, And the non-limiting features and examples of the leaving group can be found, for example, in "CAe / w (1), 2nd edition, Francis Carey (1992) » ^ 328-331 1 ; Introduction to Organic Chemistry , 2nd Edition ' Andrew Streitwieser and Clayton Heathcock (1981), pp. 169-171; and ~ (10) less, 5th edition, MCMUrry (2000)' 398 and 4 〇 8 pages; all of which are incorporated herein by reference to U.S. Patent No. s. The salt to which the organism is administered causes significant irritation and does not eliminate the biological activity and properties of the compound. In some embodiments, the salt is the acid addition salt of the compound. The medicine = can be made by reacting the compound with a mineral acid ( It is obtained by a reaction such as hydrogen dentate (for example, hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and acid acid. Pharmaceutical salt can also be made by making 158865.doc

•22· 201217392 = Substance is obtained by reaction with an organic acid such as aliphatic or aromatic retort or acid, such as formic acid, acetic acid, succinic acid, lactic acid, frequency fruit acid, tartar, citric acid , anti-bad acid, final acid, simmering acid, sulphuric acid, p-toluenesulfonic acid, salicylic acid or naphthalene sulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as an ammonium salt, an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, or an organic base ( a salt such as dicyclohexylamine, N-methyl glucosamine, gin (methyl)methylamine, C丨-C7 alkylamine cyclohexylamine, triethanolamine, ethylenediamine), and The compound is obtained by reacting with an amino acid such as arginine and lysine to form a salt. Unless otherwise expressly stated, the terms and phrases and variations thereof used in this application, particularly in the scope of the accompanying claims, are considered to be open and not restrictive. As an example of the above, the term "including" shall be taken to mean "including (not limited to)", "including (but not limited to)" or the like; as used herein, the terms "including" and "including", "including" Or "characteristically" is synonymous and inclusive or open and does not exclude other unmentioned elements or method steps; the term "having" should be interpreted as "having at least"; the term "including" should be interpreted as "including (but Not limited to); the term "instance" is used in the case of the project. (4) (4) It is detailed or restrictive early, and the terminology (such as "better", "need" or "needs" and. Words with similar meanings should not be construed as indicating that certain features are critical, basic or even important to the structure or function of the second: month, but are actually intended to emphasize only one particular implementation of the invention. Alternatives or other features that may not be used in the examples may be made. In addition, the terms "virtual /, yes," or "including at least" are interpreted synonymously. When used in relation to 158865.doc -23-201217392, the term means that the method includes at least the context of the method, the steps are recited, but may include other steps. The term 'comprising' when used in the context of a compound, composition or device means that the sigma," and the sigma or device includes at least the recited features or components (components), but may also include other features. Or a component (component). (5), unless otherwise expressly stated, the project group linked by the conjunction "and" should not be considered as requiring each of the items and each group to exist, but should be regarded as "And, or." Similarly, unless otherwise expressly stated, a group of items connected by the conjunction "or" should not be considered as a need for mutual exclusion, but should be treated as "and/or". Any plural or/or singular terms may be interpreted as singular and/or from singular to plural, depending on the context and/or application. For clarity, in this context Various singular/plural exchanges may be explicitly stated. The indefinite article "a" does not exclude the plural. A single processor or other unit may fulfill the functions of several items described in the scope of the patent application. The mere fact that certain measured values are recited in mutually different terms does not indicate that a combination of such measured values is not advantageously used. Any reference signs in the scope of the patent application shall not be construed as limiting them. - It should be understood that 'in any of the compounds described herein having one or more pairs of palmar centers, if the absolute stereochemistry is not explicitly indicated, then each The center can independently have an R configuration or an S configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched as a racemic mixture, diastereomeric, diastereomeric, or stereo. 158865.doc -24 - 201217392 Structure mixture. In addition, it is to be understood that in any of the compounds described herein having one or more double bonds that produce a geometric isomer that may be defined as an E or Z form, the 'double bonds' may independently be either E or Z or Its mixture. Also, it is to be understood that in any of the compounds described, it is intended to include all tautomeric forms. For example, it is intended to include all tautomers of the phosphate group and the thiophosphonium group. The thio-acid-decomposing tautomers Ο π- " 〇

In addition, it is intended to include the heterocyclic test substrate HS-P-〇\ and known in the art.

All tautomers' include both natural and non-natural (four) test and chimeric test tautomers. It will be appreciated that where a compound disclosed herein has a subatomic valence, it will be understood that the compound described herein can be filled with hydrogen or an isotope thereof (eg, gas) (phantom and gas 2 (gas)). Isotope labeling. Isotopes (such as phantom substitutions may provide certain therapeutic advantages due to greater metabolic stability (such as prolonged in vivo half-life or dose reduction). The chemical elements expressed in the structure of the compound can be twisted - the main one Any of the isotopes of the element can be included. For example, in the structure of a substance, a hydrogen atom can be clearly revealed or understood. In any position where a gas atom may exist in a compound, the hydrogen atom may be any isotope of hydrogen. Hydrogen-like). Therefore, unless the order of decree (not limited to) hydrogen-1 (8) and the reference of the compound covers Π:::: Exactly, 'j isotope form. 158865.doc •25· 201217392 曰... The methods and combinations described in the text include crystalline forms (also known as 曰曰 曰曰 type, which include different crystal entanglement arrangements of compounds having the same elemental composition), amorphous phase 'salts, solvates, and Hydrates. In some embodiments, the compounds described herein exist in the form of a solvate with a pharmaceutically acceptable solvent such as water, ethanol or the like. The compound is present as an unsolvated form. The solvate contains a stoichiometric or non-stoichiometric amount of solvent and can be combined with a pharmaceutically acceptable solvent such as water, ethanol or the like. Formed during the process. Forms a hydrate when the solvent is water, or forms an alcoholate when the solvent is an alcohol. Additionally, the compounds provided herein may exist in the form of unsolvates and solvates... in general, as provided herein For the purposes of the compounds and methods, the solvate forms are considered to be equivalent to the unsolvated forms. In the context of providing a range of values, it is to be understood that the upper and lower limits and the upper and lower limits of the range are Some of the examples disclosed herein relate to a compound of formula (1) or a pharmaceutically acceptable salt thereof: 158865.doc

Wherein: B1 may be an optionally substituted heterocyclic base or an optionally substituted heterocyclic test group having a protected amine group; R1 may be selected from 〇-, OH, as appropriate -26-

201217392 A substituted N-linked amino acid and optionally a substituted N-linked amino acid ester derivative; R2 may be selected from optionally substituted aryl, optionally substituted "hydroxanthyl, Optionally substituted heterocyclic groups, wherein R19, R20 and R21 may be independently absent or are ^21o-p-OR20 〇-p-OR19 hydrogen' may be; the restriction is when 〇· or oh is considered R2 is R 〇Ϊ 2. 0 Ϊ _; 尺 381 and R3b may be independently selected from hydrogen, hydrazine, optionally OR20 OR19 substituted 匚丨-6 alkyl, optionally substituted c26 alkenyl, a substituted C2-6 alkynyl group, optionally substituted Ci 6 haloalkyl and aryl (Ci 6 alkyl), or R may form an optionally substituted C3 6 cycloalkyl group together with R3b; R4 It may be selected from hydrogen, an azide group, optionally substituted Ci 6 alkyl group, optionally substituted C 2 · 6 alkenyl group and optionally substituted c 2-6 alkynyl group; R 5 may be selected from hydrogen, halogen, stack Nitro, cyano, optionally substituted C16 alkyl, -OR10 and -0C(=0)Rn; R6 may be selected from hydrogen, dentate, azide, cyano, optionally substituted Ck alkyl , -〇R12 and _〇 C( = 〇)R13; R7 may be selected from hydrogen, halogen, azide, cyano, optionally substituted C16 alkyl, -OR14 and -0C(=0)R15; or R6&R7 may be oxygen Atoms are bonded together by a carbonyl group; R8 may be selected from the group consisting of hydrogen, halogen, azido, cyano, optionally substituted Ci-6 alkyl, -OR16 and -〇c(=〇)R17; R9 may be selected from Hydrogen, azido, cyano, optionally substituted C 6 alkyl and 〇 〇 RU; R 10 , R , R , R 6 and R 18 may be independently selected from hydrogen and optionally substituted c to alkyl; R11, R13, R15&Rn may be independently selected from optionally substituted Ci.6 alkyl and optionally substituted C3.6 cycloalkyl; the limitation is 158865.doc -27· 201217392 R3a, R3b, When R4, R5, R7, Caliper 8 and R9 are all hydrogen, R6 may not be an azide group. For R2', in some embodiments, R2 may be optionally substituted heteroaryl. In other embodiments, R2 A heterocyclic group which may be optionally substituted. In other embodiments 'R2 may be an optionally substituted aryl group. For example, R2 may be optionally substituted stupid or optionally substituted naphthyl. If R2 is replaced Phenyl or substituted naphthyl, the phenyl ring and the naphthalene ring may be substituted one or more times. Suitable substituted substituents, including electron-withdrawing groups, may optionally be present on the substituted phenyl and optionally substituted naphthyl groups. And an electron withdrawing group. In some embodiments, R2 can be a substituted phenyl group. In other embodiments, R can be an unsubstituted phenyl group or an unsubstituted naphthyl group. In other embodiments, R2 can be R21〇_Y_OR20 0-P_

OR 19 wherein R19, R20 and R21 may be independently present or hydrogen, and n may be ruthenium or osmium. In some embodiments, n can be zero. In other embodiments, η may be 丨. Those skilled in the art will appreciate that when η is zero, R2 can be a cardiac thiodiphosphate group. Similarly, those skilled in the art will appreciate that when η is 1, R2 can be a cardiac thiotriphosphate group. In some embodiments, at least one of W, R2 〇 AR21 may not be present. In it: at least one of the embodiment orders and r21 may be chlorine. In some embodiments, R 〇 and R 21 may be absent. In other embodiments, the ruler 20 and may be hydrogen. In some embodiments, R1, R2G, and RZ1 may not be present. In some embodiments, the hydrogen generator should be aware of the absence of any of R, R20, and R21 'Rl9, r2. The oxygen atom to which R2 is combined may have a negative charge. For example, when r2. When not present, the oxygen atom to which 158865.doc -28- 201217392 R is combined may be 〇-. The technique depends on the substituent attached to each phosphorus atom. For example, when η is 1, α-phosphorus (the phosphorus closest to the pentose ring) can be the center of the palm. In some embodiments, α_射为为 (R) stereo的❼ In other embodiments, 4 may be (S) stereocenters. In some embodiments, may not be present. In other embodiments, ... may be hydrogen. In other embodiments, R1 can be an optionally substituted CX-amino acid. In other embodiments, R1 may be optionally substituted (X-amino acid ester derivatives. Various amino acids and amino acid ester derivatives may be used, including those described herein. Suitable for amine groups Acids include, but are not limited to, alanine, aspartic acid, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, valine, serine, and tyrosine , arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, succinic acid, tryptophan and valine. Other suitable amino acids include ( But not limited to) α-ethyl-glycine, α-propyl-glycine and β-alanine β N-linked amino acid ester derivatives include, but are not limited to, any of the following amino acids Ester derivatives: alanine, aspartic acid, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, valine, serine, tyrosine, spermine Acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. N-linked amino acid ester derivatives real These include, but are not limited to, vinegar derivatives of any of the following amino acids: alpha-ethyl-glycine, alpha-propyl-glycine, and beta-alanine. In one embodiment, R1 can be alanine. An ester derivative. In an embodiment 158865.doc -29-201217392, R丨 may be selected from the group consisting of methyl acetoacetate, ethyl acetoacetate, acetaminophen isopropyl acetate, acetamino vinegar, Methionine isopropyl vinegar and isopropyl methacrylate. In some implementations, depending on the situation, the amine acid or the optionally substituted N-linked amino acid vinegar derivative may be In other embodiments, (iv) the substituted amino acid or the optionally substituted N-linked amino acid ester derivative may be in the D configuration. In some embodiments, when R] is a visual In the case of a substituted N-linked cardioyl acid or an optionally substituted N-linked a-amino acid ester derivative, R2 may be selected from optionally substituted aryl, optionally substituted heteroaryl. And optionally substituted heterocyclic groups. In some embodiments, when R1 is an optionally substituted N-linked a-amino acid ester derivative, R2 may Optionally substituted aryl. In other embodiments, when R1 is an optionally substituted N-linked a-amino acid ester derivative, R2 may be optionally substituted heteroaryl. In the case, when R1 is an optionally substituted hydrazone-linked a-aminoester derivative, R2 may be an optionally substituted heterocyclic group. R1 may have a structure.

Wherein R22 may, in some embodiments, be selected from the group consisting of hydrogen, optionally substituted C丨.6 alkyl, optionally substituted 匸3 6 cycloalkyl, optionally substituted aryl, optionally substituted aryl a base (Cl 6 ) and optionally substituted C 6 haloalkyl; and R 23 may be selected from nitrogen, optionally substituted CI 6 alkyl, optionally substituted C 16 dent alkyl, optionally substituted C : 3·6 cycloalkyl, optionally substituted C6 aryl, optionally substituted Cw aryl and optionally substituted aryl (Ci 6 alkyl); and R24 may be hydrogen or optionally substituted The Cm alkyl group; or R23, together with R24, 158865.doc -30-201217392 form an optionally substituted C3_6 cycloalkyl group. When R has the structure shown above, R23 may be optionally substituted Cw alkyl. Examples of suitable substituted 2Ci.6 alkyl groups, as appropriate, include optionally substituted variants of the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third Butyl, pentyl (branched and straight) and hexyl (branched and linear). When R.sup.23 is substituted, R.sup.23 may be substituted with one or more substituents selected from the group consisting of N-decylamino, fluorenyl, alkylthio, optionally substituted aryl, hydroxy, optionally substituted heteroaryl. Base, oxime carboxyl group and amine group. In a certain implementation, R23 may be an unsubstituted heart-burning group such as methyl, ethyl, n-propyl, isopropyl-n-butyl, isobutyl, tert-butyl, pentyl (branched chain and straight Chain) and hexyl (branched chain and linear chain). In one embodiment, R23 can be a methyl group. For R22' In some embodiments, R22 can be an optionally substituted Cl-6 alkyl group. Examples of the C1·6 alkyl group which may be optionally substituted include a substituted m, an ethyl group, a n-propyl group, an isopropyl group, a n-t-butyl isobutyl group, a second butyl group, a pentyl group (branched chain and straight). Chain) and hexyl (branched chain and direct bond). In some embodiments, r22 can be methyl or isopropyl. In the second embodiment, R22 may be ethyl or neopentyl. In other embodiments, t R may be optionally substituted c: 3·6 cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl include variants of the following groups which are optionally substituted: Cyclopropyl In one embodiment, R22 can be an optionally substituted cyclohexyl group. In other embodiments, R22 can be an aryl group such as phenyl and naphthyl. In other embodiments, 'R22 can be an optionally substituted aryl group m)e. In some embodiments 158865.doc -31 - 201217392, R 2 2 -r is a poorly substituted benzyl group. In some embodiments R may be optionally substituted Ci6 dentate alkyl, such as CF3. In some embodiments, R24 can be hydrogen. In other embodiments, R24 can be optionally substituted C!.4 alkyl such as methyl, ethyl, n-propyl, isoindolyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R can be a methyl group. In some embodiments, R23, together with R24, can form a Cw cycloalkyl group that is optionally substituted. Example G of the optionally substituted c3-6 cycloalkyl group includes optionally substituted variants of the following groups: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Depending on the group selected for R23 & R24, the carbon to which R23 and R24 are attached may be the center of the palm. In certain embodiments, the carbon to which R23 and R24 are attached may be the (R) pair of palmar centers. In other embodiments, the carbon to which R23 and R24 are attached may be (3) in the palm of the hand R22h R23 〇24

Examples of R220 R (3 Io' m 〇 groups include the following:

〇 ΗΝ—^ H3C〇

Ο ΗΝ-

158865.doc ·32· 201217392

The substituent attached to the 5' position of the compound of formula (I) may vary. In some embodiments, 113& and 11315 may be the same. In other embodiments, R3a is different from R3b玎. In some embodiments, both R3a and R3b can be hydrogen. In some embodiments, and R3b are at least based; and the other of R3a&R3b can be hydrogen as appropriate. Examples of suitably substituted Ck alkyl groups include optionally substituted variants of the following groups: methyl, ethyl, n-propyl, iso-, n-butyl, isobutyl, tert-butyl Base, pentyl (branched and linear) and hexyl (branched and linear). In one embodiment, at least one of R3a & R3b can be a methyl group, and the other of RSa and R3b can be hydrogen. In other embodiments, at least one of R3a and R3b may be optionally substituted C -6 haloalkyl, and the other of 尺 33 and R 3b may be hydrogen. An example of a suitable South-based base that is suitable for replacement is cf3. In other embodiments, R3a, together with R3b, can form an optionally substituted C3-6 cycloalkyl group. When t is attached to a substituent on the 5' carbon such that the 5 carbons are palm to palm, in some embodiments, 5, the carbon may be the (R) stereocenter. In other embodiments, 5, carbon can be (S) stereocentric. Connected to 4, the substituents can vary. In the case of - (4), the r4 may be argon. In other embodiments, R4 can be an azide group. In other embodiments, R.sup.4 may be optionally substituted cw-based such as optionally substituted for the following groups: methyl 'ethyl, n-propyl, isopropyl n-butyl, isobutyl Butyl, pentyl (branched and straight) and hexyl (branched and straight). In some embodiments, r4 can be a non-diluted group as appropriate. In two embodiments, R4 can be a C6 6 fast group that is optionally substituted. The substituents 5 to 2, carbon and 3, carbon may also vary. In some embodiments 'R5 can be hydrogen. In other embodiments, the ruler 5 can be a fang. In other embodiments, R can be an azide group. In other embodiments, r5 can be an aryl group. The following groups are optionally substituted with isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight) and base (branched and straight). In other embodiments, r5 can be a view 10, where R1. It can be hydrogen. In other embodiments, r5 can be _〇r1. Wherein Ri0 may be a C16 alkyl group substituted as it is. In other embodiments, r5 can be 〇C(〇)R ′ where R can be optionally substituted C, .6 alkyl or, if appropriate, substituted C3·6 cycloalkyl. Examples of suitable k-based and c3.6 cycloalkyl groups are described herein. In the second embodiment, 'R may be optionally substituted Cl.6 alkyl, such as methyl, ethyl, n-propyl 158865.doc-34-201217392. In some embodiments, the ruler 6 may be A. hydrogen. In other embodiments, R6 can be a halogen. In other embodiments, 6^, r6...R is an azide group. In other embodiments, it is chaotic. In some embodiments, R6 may be substituted as appropriate. In other embodiments, 'r6 may be 12, wherein ^ may be ammonia. In other embodiments, R6 may be _〇Rl2 , wherein it can be replaced by a base. It is ice 2 (wherein Rl2 can be a Cw pit base which is optionally substituted); a non-limiting list of examples is methoxy, ethoxy, n-propoxy a base, isopropoxy, n-butoxy 'isobutoxy and a third butoxy group, a silk group (money or branching bond) and a hexyloxy group (a straight or branched bond). In other embodiments, R6 It may be 〇c(tetra)Rl3, wherein r13 may be a substituted or substituted core (IV) group as appropriate. Suitable: Examples of substituted alkyl groups include the following groups. Substituted variants: methyl 'ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and linear) and hexyl (branched and linear) Examples of suitably substituted c36 cycloalkyl groups include optionally substituted variants of the following groups: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In other embodiments, r7 may be a functional element. In other embodiments, V may be an azide group. In other embodiments, 'r7 may be a cyano group. In the example, r7 may be Optionally substituted Cl-6 alkyl. In other embodiments, R7 can be -OR. In one embodiment, although R is hydrogen, R7 can be a hydroxyl group. In other embodiments, when If the Ci 6 group is substituted, R? may be an optionally substituted 6 alkoxy group, which is -OR14 (wherein Ru may be optionally substituted C16 alkyl group) 158865.doc -35 - 201217392 Examples of R7 include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy (straight bond or a knife bond) and a hexyloxy group (straight bond or branch bond). In other embodiments, R7 may be -〇C(=0)i^, wherein R]5 may be optionally substituted d6 alkyl , such as the following groups of substituted groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and linear) And hexyl (branched chain and straight chain). In some embodiments, R7 can be 〇C(-〇)R' wherein R1S can be optionally substituted 匸36 环. In some embodiments, R8 can be hydrogen. In other embodiments, r8 In other embodiments, 'R8 can be a nitrogen group. In other embodiments, R8 can be a cyano group. In some embodiments, R8 can be _〇Rl6. When the ruler 6 is hydrogen 'R8 may be a thiol group. Or, when Rl6 is optionally substituted c "alkyl group" R8 may be optionally substituted CM oxy group. Suitable for the hospital oxy group is described herein. R8 may be an optionally substituted alkyl group. In other embodiments, R8 may be _〇c(= 〇)Rl7, wherein R7 is an optionally substituted Ci6 alkyl group. In other implementations, r8 can be: 〇C( 〇)R ’ where Rl7 is the c3.6 ring-based base that is optionally replaced. Examples of suitable C丨·6 alkyl groups and C:3·6 cycloalkyl groups are described herein. In some embodiments, both 'R6 and R7 may be a trans-base. In other embodiments, R and R may both be oxygen atoms and are joined together by a plurality of groups, for example, θα ο) Ο In some embodiments, at least one of Rw may be a halogen. In some embodiments, 'R7 and Μ are both dentates. In other embodiments R may be dentate and R8 may be an optionally substituted 6 alkyl group, such as I58865.doc

-36 - 201217392 1 =:人. In other embodiments, R7 can be hydrogen and R8 can be dentate. In one embodiment, at least one of the cores 7 may be a thiol group and the oxime may be replaced by a p 7 W alkyl group. In other embodiments, R6 can be a hydroxyl soil, R can be a radix, H or dentate, and R8 can be an optionally substituted Cl6 succinyl group. In some embodiments, 'R3a, R3b, R4, a r9 may be hydrogen in any of the embodiments described in this paragraph. In some embodiments, any of the embodiments of B1 described in this paragraph may be replaced by adenoids as appropriate, replaced by conditions, and replaced by a conditional (iv), as appropriate. Cytosine or uracil as appropriate. In a two-part embodiment, R can be hydrogen. In other embodiments, R9 can be an azide group 9. In other embodiments, R9 can be a cyano group. In other embodiments, R9 can be an optionally substituted Ci. 6 alkyl group, such as described herein. In some embodiments, R9 can be _0Rl8. In some embodiments, when R9 is -OR, R9 can be a hydroxyl group. In other embodiments, when r9 is _〇Ri8, R9 can be an optionally substituted Cw alkoxy group. Examples of optionally substituted C!-6 alkoxy include the following: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy , pentyloxy (branched chain and direct bond) and hexyloxy (branched chain and linear chain). A variety of optionally substituted heterocyclic bases can be attached to the pentose ring. In some embodiments, one or more amine and/or amine groups can be protected with a suitable protecting group. For example, an amine group can be protected by converting an amine and/or an amine group to a guanamine or amino carboxylic acid vinegar. In some embodiments, optionally substituted heterocyclic bases or optionally substituted heterocyclic bases having one or more protected amine groups can have one of the following structures: 158865.doc -37 · 201217392

Wherein: RA2 may be selected from the group consisting of hydrogen, halogen and NHRJ2, wherein RJ2 may be selected from the group consisting of hydrogen, -C(=0)RK2 and -C(=〇)〇RL2; RB2 may be halogen or NhRW2, wherein R is selected from hydrogen, Substituted substituted Cl_6 alkyl, optionally substituted C2. 6 alkenyl, optionally substituted c38 cycloalkyl, ·c(= 〇) rm2 and -C(= 0) 〇RN2; RC2 can be Hydrogen or nhr〇2, wherein r〇2 may be selected from the group consisting of hydrogen, —C(=0)RP2 and _C(=0)〇RQ2; rD2 may be selected from hydrogen, halogen, optionally substituted c _6 alkyl , optionally substituted C 2 6 alkenyl and optionally substituted C: 2_6 alkynyl; may be selected from hydrogen, optionally substituted Ci. 6 alkyl, optionally substituted C 3-8 cycloalkyl, -C(=0)RR2 and -C(=〇)〇RS2 ; RF2 may be selected from hydrogen, dentate, optionally substituted CM alkyl, optionally substituted Cm alkenyl, and optionally substituted Gw Alkynyl; γ2 may be N (nitrogen) or CR12 ' wherein R12 may be selected from hydrogen, halogen, optionally substituted ci 6 alkyl 'optionally substituted C2_6 alkenyl and optionally substituted c26 alkynyl; RG2 may be optionally substituted Cl. 6 alkyl; RH2 may be hydrogen or ]^111^2, which may be independently selected Hydrogen, C(= 〇)rU2 and _c(= 〇)〇rV2, and 158865.doc •38· 201217392 RK2, P2 H-, RQ2, rR2, rS2, rU2 and rV2 may be independently selected from Cl_6 alkyl , c2-6 alkenyl, c2.6 alkynyl, c3 6 cycloalkyl, C3-6 cycloalkenyl, c: 3·6 cycloalkynyl, C6_1 fluorene, heteroaryl, heteroalicyclic, aromatic a group (C!-6 alkyl), a heteroaryl (Cl. 6 alkyl) and a heteroalicyclic (c^alkyl) group. In some embodiments, the structures shown above may be modified by replacing one or more hydrogens with a substituent selected from the list of substituents provided for the definition of "substituted". Suitable optionally substituted c10 alkyl groups which may be present on a optionally substituted heterocyclic base or an optionally substituted heterocyclic base having one or more protected amine groups are described herein, And includes variants of the following groups which are optionally substituted: methyl, ethyl, n-propyl, isopropyl n-butyl, isobutyl, tert-butyl, pentyl (branched and linear) and Hexyl (branched chain and linear chain). In some embodiments, B1 can be selected from the group consisting of adenine, guanine, chest biting, cellulite, and urinary blasting. In some embodiments, 'rB2 can be cis-2. In other implementations, you may be hydrogen. In some embodiments, B1 may be

N NH, 〇

NH in other embodiments may be

. In some embodiments, N N 'H In some embodiments, βΐ can be /158865.doc • 39- 201217392 NHRW2

N B1 may be / '° In other embodiments 'B1 may be I Ν' 'Nh2 νη2 ΝΗ I In other embodiments 丨 may be II I . In some implementations ο

N

IjJ \〇 example,

RH2 In some embodiments, when R2 is a substituted or unsubstituted phenyl group, R1 may not be '. In its 〇HN—^′, is }-( Ο HN—^ In other embodiments, when R 2 is substituted or not written h3co. Instead of phenyl and hi-丨, at least r5 and r6 - No; his case 2 'When the ruler 2 is a substituted or unsubstituted stupid base, R1 cannot be A >~( ..

R21〇—P In some R cases, when R】is 〇. or 0H, r2 is not Ρ—OR19 OR20 5 In some embodiments, at least one of the feet 33 and R3b may not be hydrogen. In some embodiments, 'Μ is not an azide group. In some cases, when & is an azide group, RW is not ^e at three. In the case of a case where tR4 is an azide group, B1 is not a conditionally substituted urinary D pyridine, and one or more protected amine groups are optionally substituted for urinary 158S65.doc 201217392 bite, as the case may be. Substituted cytosine or optionally substituted cytosine with one or more protected amine groups. In some embodiments, R6 may not be an azide group. In some embodiments 'when R1 is methyl ester of glycine, alanine, valine or phenylalanine; R2 is p-phenyl or p-nitrophenyl; B1 is thymine; and R3a, R3b, r4 When r5, r7, uldent 8 and r9 are all hydrogen, "not" T is an azide group. In some embodiments, at least one of R6 and R7 may not be a hydroxyl group. For example, R6 may not be a hydroxyl group. R7 may not be a hydroxyl group, or neither R6 nor R7 may be a hydroxyl group. Some embodiments disclosed herein relate to a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein: B1 may be as described in paragraph [0106] Said optionally substituted heterocyclic base; R1 may be selected from 〇-, 0H, optionally substituted amino acid and optionally substituted N-linked amino acid ester derivative 'R may be selected from Substituted aryl and r2i〇_

T. OR 20

OR 19 wherein R19, R20 and R21 may be independently absent or hydrogen, and n may be 〇 or 1; the restriction is that when R1 is 〇- or 0Η, R2 is R21〇_j___〇_|_ OR2

OR 19 and R may be hydrogen; R 4 may be hydrogen; R 5 may be selected from hydrogen, south, optionally substituted Q·6 alkyl and 〇R^; R6 may be selected from hydrogen, dentate, optionally Substituted C丨.6 alkyl, n_0C(=0)Rl3; r7 may be selected from hydrogen halogen, aryl group, cyano group, optionally substituted C14 group, _or14 and 〇C(= 〇)R' Is an oxygen atom and is connected to (4); R8 may be selected from hydrogen, dentate, optionally substituted Cl, alkyl and _ORl6; R9 may be hydrogen, "" and ~ 蜀 is selected from hydrogen and 158865 .doc • 41- 201217392 Alternately substituted Cl.6 alkyl; and ampules, 3 and Rl5, may be independently selected from optionally substituted C 1-6 alkyl and, where appropriate, icy cycloalkyl. Some embodiments disclosed herein are those relating to a compound of formula (I) or a pharmaceutically acceptable salt thereof: B: may be a heterocyclic test group selected from the group consisting of the following: Replacement of the heterocyclic test: N, 1

CH«

»Λ/ν\Λ

'R may be selected from hydrazine, hydrazine, optionally substituted hydrazine-linked amino acid, and optionally substituted hydrazine-linked amino acid R2 may be selected from optionally substituted aryl groups, wherein R19, R20 And R2! may be independently absent or be a derivative of the formula r21o-ρ-OR19 hydrogen, f ηΓ ί °1 or 1; the restriction is that when Rl is 〇- or OH, R2 is R 〇P —[〇 P -, 1133 and R3b may be hydrogen; r4 may be hydrogen; r5 may be selected from OR2

OR hydrogen, halogen, optionally substituted C,·6 alkyl and -OR1〇; R6 may be selected from hydrogen, dentate, optionally substituted C丨·6 alkyl, —〇R12 and 〇〇c ( R〇) r13 ; R7 may be selected from the group consisting of hydrogen, halogen, azido, cyano, optionally substituted C16 alkyl, -OR14 and -OC(=0)R15; or R6 and R7 may both be oxygen atoms and Linked together by a carbonyl group; R8 may be selected from hydrogen, halogen, optionally substituted c ι 6 158865.doc • 42- 201217392 alkyl and -OR16; R9 may be hydrogen; R10, R12, Rl4 and Rl6 may independently It is selected from the group consisting of hydrogen and optionally substituted 〇1·6 alkyl; XR13&R15 can be independently selected from optionally substituted C!-6 alkyl and optionally substituted c3 6 cycloalkyl. In some embodiments, Formula (I) can be a compound of formula (Ια), wherein: B1 can be an optionally substituted heterocyclic base selected from the group consisting of: or an optionally substituted heterocyclic group having a protected amine group Ring base: cytosine, uridine, thoracic, guanine and adenine; R1 may be selected from 〇-, OH, and alkaloid, proline or leucine, optionally substituted N-linked amine a carboxylic acid ester derivative; R2 may be selected from optionally substituted phenyl, optionally substituted naphthyl, optionally substituted. Quino base and 21 J] R °~P\1·°~P\~, where R19, R20 and R21 can be independently hydrogen or no OR20 〇R19, and η May be 0 or 1 r21o-ρ- OR2 o-P-OR19; the restriction is that when R1 is 0 or OH, R2 is R3a& R3b can be hydrogen; R4 can be hydrogen; R5 can be hydrogen; R6 can be -OR12 or _〇C(=0)R"; may be selected from halogen, _〇r14 and -0C(=0)R15; R8 may be an optionally substituted alkyl group; R9 may be hydrogen; R12 and R14 may Independently hydrogen or optionally substituted C 6 alkyl; and R 13 and R 15 may independently be optionally substituted C c alkyl. Some embodiments relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: B1 may be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having a protected amine group. R1 may be selected from 〇·, 〇H, optionally substituted N-linked amino acids, and optionally substituted n-linked amino acid ester derivatives; R2 may be selected from optionally substituted aryl groups. Depending on the situation 158865.doc • 43· 201217392 R21〇_p_ OR20 Condition 9 takes "diarylaryl" optionally substituted heterocyclic group and iRl9 wherein R, r21r21 can be independently absent or hydrogen, and It can be 0 or 1; the restriction condition is that when R1 is Ο- or OH, the ruler 2 is; R3lR3b can be independently selected from A, as the case may be taken - p--OR20 0-p-- OR19 (4) Substituting one of the dilute groups as appropriate. The C2·6 alkynyl group, optionally substituted Cl.6, and the aryl group and the aryl group, or R3a, may be formed together with R3b as appropriate. The substituted cycloalkyl π may be selected from the group consisting of hydrogen, an azide group, optionally substituted Ci6 alkyl, optionally substituted C2.6 alkenyl, and optionally substituted 匕6 alkynyl. R5 may be selected from the group consisting of hydrogen, halogen, azido, cyano, optionally substituted Ci.6, 〇r1, and -〇C(=〇)RU; R6 may be selected from hydrogen, dentate, Azido group, azo group, optionally substituted CN6 alkyl group, _0Ri2 and 〇(:(=〇)κη; r7 may be selected from hydrogen, dentate, azide group, an aryl group, and optionally substituted ci6 The alkyl group, _〇rU and -〇'(=〇)ιι15; may be all oxygen atoms and are linked together by several groups; R8 may be selected from hydrogen, dentate, azide group, cyano group, and optionally substituted Cw alkyl, -ORW and -〇C(=〇)Rl7; r9 may be selected from hydrogen azide cyano, optionally substituted alkyl and 〇Rl8; RlG, Rn, R丨4, R and R It may be independently selected from hydrogen and optionally substituted Cw alkyl; and R, R, R15 and R17 may independently be optionally substituted Cw alkyl and, as appropriate, substituted (: 3.6 cycloalkyl. In some embodiments, the compound of formula (I) may be a single diastereomer. In other embodiments, the compound of formula (I) may be a mixture of diastereomers 158865.doc • 44·201217392. In some embodiments, the compound of formula (i) can be two diastereomeric a 1:1 mixture of the constructs. In some embodiments, the compound of formula (I) may be enriched by diastereomerization (eg, one diastereomer may be compared to other diastereomers) The total concentration is present at a concentration of > 55%, 275%, 280%, 290%, 295%, 298% or 299%.) R1 and R2 of the compound of formula (I) or a pharmaceutically acceptable salt thereof Some examples are provided in Table 1. Tables 2 to 4 provide the structures of the variables bb01-bbl2, aaOl-aall, and es01-esl4, respectively. For example, the first entry in Table 1 is "bb01, aa01, es01", which corresponds to the compound of formula (I), where R2 is • KD ' and ... is. Table 1 R'R'Ra R2, R', Ra R'R'Ra R2, R\Ra R'R'Ra bb01, aa01, es01 bb03, aa01, es01 bb05, aa01, es01 bb07, aa01, es01 bb09, Aa01,es01 bb01,aa01,es02 bb03,aa01,es02 bb05,aa01,es02 bb07,aa01,es02 bb09,aa01,es02 bb01,aa01,es03 bb03,aa01,es03 bb05,aa01,es03 bb07,aa01,es03 bb09, Aa01,es03 bb01,aa01,es04 bb03,aa01,es04 bb05,aa01,es04 bb07,aa01,es04 bb09,aa01,es04 bb01,aa01,es05 bb03,aa01,es05 bb05,aa01,es05 bb07,aa01,es05 bb09, Aa01,es05 bb01,aa01,es06 bb03,aa01,es06 bb05,aa01,es06 bb07,aa01,es06 bb09,aa01,es06 bb01,aa01,es07 bb03,aa01,es07 bb05,aa01,es07 bb07,aa01,es07 bb09, Aa01,es07 bb01,aa01,es08 bb03,aa01,es08 bb05,aa01,es08 bb07,aa01,es08 bb09,aa01,es08 bb01,aa01,es09 bb03,aa01,es09 bb05,aa01,es09 bb07,aa01,es09 bb09, Aa01,es09 bb01,aa01,esl0 bb03,aa01,esl0 bb05,aa01,esl0 bb07,aa01,esl0 bb09,aa01,esl0 bb01,aa01,esll bb03,aa01,esll bb05,aa01,esll bb07,aa01 Esll bb09,aa01,esll bb01,aa01,esl2 bb03,aa01,esl2 bb05,aa01,esl2 bb07,aa01,esl2 bb09,aa01,esl2 bb01,aa02,es01 bb03,aa02,es01 bb05,aa02,es01 bb07,aa02, Es01 bb09,aa02,es01 bb01,aa02,es02 bb03,aa02,es02 bb05,aa02,es02 bb07,aa02,es02 bb09,aa02,es02 bb01,aa02,es03 bb03,aa02,es03 bb05,aa02,es03 bb07,aa02, Es03 bb09,aa02,es03 bb01,aa02,es04 bb03,aa02,es04 bb05,aa02,es04 bb07,aa02,es04 bb09,aa02,es04 bb01,aa02,es05 bb03,aa02,es05 bb05,aa02,es05 bb07,aa02, Es05 bb09,aa02,es05 bb01,aa02,es06 bb03,aa02,es06 bb05,aa02,es06 bb07,aa02,es06 bb09,aa02,es06 bb01,aa02,es07 bb03,aa02,es07 bb05,aa02,es07 bb07,aa02, Es07 bb09,aa02,es07 bb01,aa02,es08 bb03,aa02,es08 bb05,aa02,es08 bb07,aa02,es08 bb09,aa02,es08 bb01,aa02,es09 bb03,aa02,es09 bb05,aa02,es09 bb07,aa02, Es09 bb09,aa02,es09 bb01,aa02,esl0 bb03,aa02,esl0 bb05,aa02,esl0 bb07,aa02,esl0 bb09?aa02,esl0 bb01,aa02,esll bb03,aa02,esll bb05,aa02,esll bb07,aa02, Esll bb09,a A02,esl 1 bb01,aa02,esl2 bb03,aa02,esl2 bb05,aa02,esl2 bb07,aa02,esl2 bb09,aa02,esl2 158865.doc •45- 201217392 R'R'Ra R'R'Ra Κ',Κ ',Κα R\R\Ra R'R'Ra bb01,aa03,es01 bb03,aa03,es01 bb05,aa03,es01 bb07,aa03,es01 bb09,aa03,es01 bb01,aa03,es02 bb03,aa03,es02 bb05, Aa03,es02 bb07,aa03,es02 bb09,aa03,es02 bb01,aa03,es03 bb03,aa03,es03 bb05,aa03,es03 bb07,aa03,es03 bb09,aa03,es03 bb01,aa03,es04 bb03,aa03,es04 bb05, Aa03,es04 bb07,aa03,es04 bb09,aa03,es04 bb01,aa03,es05 bb03,aa03,es05 bb05,aa03,es05 bb07,aa03,es05 bb09,aa03,es05 bb01,aa03,es06 bb03,aa03,es06 bb05, Aa03,es06 bb07,aa03,es06 bb09,aa03,es06 bb01,aa03,es07 bb03,aa03,es07 bb05,aa03,es07 bb07,aa03,es07 bb09,aa03,es07 bb01,aa03,es08 bb03,aa03,es08 bb05, Aa03,es08 bb07,aa03,es08 bb09,aa03,es08 bb01,aa03,es09 bb03,aa03,es09 bb05,aa03,es09 bb07,aa03,es09 bb09,aa03,es09 bb01,aa03,esl0 bb03,aa03,esl0 bb05, Aa03, esl0 bb07, aa03, esl0 bb09, aa03, esl0 bb01, aa03, es Ll bb03,aa03,esll bb05,aa03,esll bb07,aa03,esll bb09,aa03,esll bb01,aa03,esl2 bb03,aa03,esl2 bb05,aa03,esl2 bb07,aa03,esl2 bb09,aa03,esl2 bb01,aa04, Es01 bb03,aa04,es01 bb05,aa04,es01 bb07,aa04,es01 bb09,aa04,es01 bb01,aa04,es02 bb03,aa04,es02 bb05,aa04,es02 bb07,aa04,es02 bb09,aa04,es02 bb01,aa04, Es03 bb03,aa04,es03 bb05,aa04,es03 bb07,aa04,es03 bb09,aa04,es03 bb01,aa04,es04 bb03,aa04,es04 bb05,aa04,es04 bb07,aa04,es04 bb09,aa04,es04 bb01,aa04, Es05 bb03,aa04,es05 bb05,aa04,es05 bb07,aa04,es05 bb09,aa04,es05 bb01,aa04,es06 bb03,aa04,es06 bb05,aa04,es06 bb07,aa04,es06 bb09,aa04,es06 bb01,aa04, Es07 bb03,aa04,es07 bb05,aa04,es07 bb07,aa04,es07 bb09,aa04,es07 bb01,aa04,es08 bb03,aa04,es08 bb05,aa04,es08 bb07,aa04,es08 bb09,aa04,es08 bb01,aa04, Es09 bb03,aa04,es09 bb05,aa04,es09 bb07,aa04,es09 bb09,aa04,es09 bb01,aa04,esl0 bb03,aa04,esl0 bb05,aa04,esl0 bb07,aa04,esl0 bb09,aa04, Esl0 bb01,aa04,esll bb03,aa04,esll bb05,aa04,esll bb07,aa04,esll bb09,aa04,esll bb01,aa04,esl2 bb03,aa04,esl2 bb05,aa04,esl2 bb07,aa04,esl2 bb09,aa04, Esl2 bb01,aa05,es01 bb03,aa05,es01 bb05,aa05,es01 bb07,aa05,es01 bb09,aa05,es01 bb01,aa05,es02 bb03,aa05,es02 bb05,aa05,es02 bb07,aa05,es02 bb09,aa05, Es02 bb01,aa05,es03 bb03,aa05,es03 bb05,aa05,es03 bb07,aa05,es03 bb09,aa05,es03 bb01,aa05,es04 bb03,aa05,es04 bb05,aa05,es04 bb07,aa05,es04 bb09,aa05, Es04 bb01,aa05,es05 bb03,aa05,es05 bb05,aa05,es05 bb07,aa05,es05 bb09,aa05,es05 bb01,aa05,es06 bb03,aa05,es06 bb05,aa05,es06 bb07,aa05,es06 bb09,aa05, Es06 bb01,aa05,es07 bb03,aa05,es07 bb05,aa05,es07 bb07,aa05,es07 bb09,aa05,es07 bb01,aa05,es08 bb03,aa05,es08 bb05,aa05,es08 bb07,aa05,es08 bb09,aa05, Es08 bb01,aa05,es09 bb03,aa05,es09 bb05,aa05,es09 bb07,aa05,es09 bb09,aa05,es09 bb01,aa05,esl0 bb03, Aa05,esl0 bb05,aa05,esl0 bb07,aa05,esl0 bb09,aa05,esl0 bb01,aa05,esll bb03,aa05,esll bb05,aa05,esll bb07,aa05,esll bb09,aa05,esll bb01,aa05,esl2 bb03, Aa05,esl2 bb05,aa05,esl2 bb07,aa05,esl2 bb09,aa05,esl2 bb01,aa06,es01 bb03,aa06,es01 bb05,aa06,es01 bb07,aa06,es01 bb09,aa06,es01 bb01,aa06,es02 bb03, Aa06,es02 bb05,aa06,es02 bb07,aa06,es02 bb09,aa06,es02 bb01,aa06,es03 bb03,aa06,es03 bb05,aa06,es03 bb07,aa06,es03 bb09,aa06,es03 bb01,aa06,es04 bb03, Aa06,es04 bb05,aa06,es04 bb07,aa06,es04 bb09,aa06,es04 bb01,aa06,es05 bb03,aa06,es05 bb05,aa06,es05 bb07,aa06,es05 bb09,aa06,es05 bb01,aa06,es06 bb03, Aa06,es06 bb05,aa06,es06 bb07,aa06,es06 bb09,aa06,es06 bb01,aa06,es07 bb03,aa06,es07 bb05,aa06,es07 bb07,aa06,es07 bb09,aa06,es07 bb01,aa06,es08 bb03, Aa06,es08 bb05,aa06,es08 bb07,aa06,es08 bb09,aa06,es08 bb01,aa06,es09 bb03,aa06,es09 bb05,aa06,es09 bb07,aa06,es09 Bb09,aa06,es09 bb01,aa06,esl0 bb03,aa06,esl0 bb05,aa06,esl0 bb07,aa06,esl0 bb09,aa06,esl0 bb01,aa06,esll bb03,aa06,esll bb05,aa06,esll bb07,aa06,esll Bb09,aa06,esll 158865.doc • 46- 201217392 R2,R*,Ra R'R1,!^ ΙΐΆΚα R2,R\Ra bb01,aa06,esl2 bb03,aa06,esl2 bb05,aa06,esl2 bb07,aa06,esl2 Bb09,aa06,esl2 bb01,aa07,es01 bb03,aa07,es01 bb05,aa07,es01 bb07,aa07,es01 bb09,aa07,es01 bb01,aa07,es02 bb03,aa07,es02 bb05,aa07,es02 bb07,aa07,es02 Bb09,aa07,es02 bb01,aa07,es03 bb03,aa07,es03 bb05,aa07,es03 bb07,aa07,es03 bb09,aa07,es03 bb01,aa07,es04 bb03,aa07,es04 bb05,aa07,es04 bb07,aa07,es04 Bb09,aa07,es04 bb01,aa07,es05 bb03,aa07,es05 bb05,aa07,es05 bb07,aa07,es05 bb09,aa07,es05 bb01,aa07,es06 bb03,aa07,es06 bb05,aa07,es06 bb07,aa07,es06 Bb09,aa07,es06 bb01,aa07,es07 bb03,aa07,es07 bb05,aa07,es07 bb07,aa07,es07 bb09,aa07,es07 bb01,aa07,es08 bb03,aa07,es08 bb05,aa07,es08 b B07,aa07,es08 bb09,aa07,es08 bb01,aa07,es09 bb03,aa07,es09 bb05,aa07,es09 bb07,aa07,es09 bb09,aa07,es09 bb01,aa07,esl0 bb03,aa07,esl0 bb05,aa07,esl0 Bb07,aa07,esl0 bb09,aa07,esl0 bb01,aa07,esll bb03,aa07,esll bb05,aa07,esll bb07,aa07,esll bb09,aa07,esll bb01,aa07,esl2 bb03,aa07,esl2 bb05,aa07,esl2 Bb07,aa07,esl2 bb09,aa07,esl2 bb01,aa08,es01 bb03,aa08,es01 bb05,aa08,es01 bb07,aa08,es01 bb09,aa08,es01 bb01,aa08,es02 bb03,aa08,es02 bb05,aa08,es02 Bb07,aa08,es02 bb09,aa08,es02 bb01,aa08,es03 bb03,aa08,es03 bb05,aa08,es03 bb07,aa08,es03 bb09,aa08,es03 bb01,aa08,es04 bb03,aa08,es04 bb05,aa08,es04 Bb07,aa08,es04 bb09,aa08,es04 bb01,aa08,es05 bb03,aa08,es05 bb05,aa08,es05 bb07,aa08,es05 bb09,aa08,es05 bb01,aa08,es06 bb03,aa08,es06 bb05,aa08,es06 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bb08,aa07,es02 bbl0,aa07,es02 bb02,aa07,es03 bb04,aa07,es03 bb06,aa07,es03 bb08,aa07,es03 bbl0,aa07 ,es03 bb02,aa07,es04 bb04,aa07,es04 bb06,aa07,es04 bb08,aa07,es04 bbl0,aa07,es04 bb02,aa07,es05 bb04,aa07,es05 bb06,aa07,es05 bb08,aa07,es05 bbl0,aa07 ,es05 bb02,aa07,es06 bb04,aa07,es06 bb06,aa07,es06 bb08,aa07,es06 bbl0,aa07,es06 bb02,aa07,es07 bb04,aa07,es07 bb06,aa07,e S07 bb08,aa07,es07 bbl0,aa07,es07 bb02,aa07,es08 bb04,aa07,es08 bb06,aa07,es08 bb08,aa07,es08 bbl0,aa07,es08 bb02,aa07,es09 bb04,aa07,es09 bb06,aa07, Es09 bb08,aa07,es09 bbl0,aa07,es09 bb02,aa07,esl0 bb04,aa07,esl0 bb06,aa07,esl0 bb08,aa07,esl0 bbl0,aa07,esl0 bb02,aa07,esll bb04,aa07,esll bb06,aa07, Esll bb08,aa07,esll bbl0,aa07,esll bb02,aa07,esl2 bb04,aa07,esl2 bb06,aa07,esl2 bb08,aa07,esl2 bbl0,aa07,esl2 bb02,aa08,es01 bb04,aa08,es01 bb06,aa08, Es01 bb08,aa08,es01 bbl0,aa08,es01 bb02,aa08,es02 bb04,aa08,es02 bb06,aa08,es02 bb08,aa08,es02 bbl0,aa08,es02 bb02,aa08,es03 bb04,aa08,es03 bb06,aa08, Es03 bb08,aa08,es03 bbl0,aa08,es03 bb02,aa08,es04 bb04,aa08,es04 bb06,aa08,es04 bb085aa08,es04 bbl0,aa08,es04 bb02,aa08,es05 bb04,aa08,es05 bb06,aa08,es05 bb08 ,aa08,es05 bbl0,aa08,es05 bb02,aa08,es06 bb04,aa08,es06 bb06,aa08,es06 bb08,aa08,es06 bbl0,aa08,es06 bb02,aa08,es07 bb04,aa08,es07 bb06,aa08,es07 bb08 ,aa08,es07 bbl0,aa08,es07 bb02,aa08,es08 Bb04,aa08,es08 bb06,aa08,es08 bb08,aa08,es08 bbl0,aa08,es08 158865.doc -49- 201217392 R'R'Ra R2,R\Ra R2,R\Ra R2,R\Ra R2,R \Ra bb02,aa08,es09 bb04,aa08,es09 bb06,aa08,es09 bb08,aa08,es09 bbl0,aa08,es09 bb02,aa08,esl0 bb04,aa08,esl0 bb06,aa08,esl0 bb08,aa08,esl0 bbl〇, Aa08,esl0 bb02,aa08,esll bb04,aa08,esll bb06,aa08,esll bb08,aa08,esll bbl0,aa08,esll bb02,aa08,esl2 bb04,aa08,esl2 bb06,aa08,esl2 bb08,aa08,esl2 bbl0, Aa08,esl2 bb02,aa09,es01 bb04,aa09,es01 bb06,aa09,es01 bb08,aa09,es01 bbl0,aa09,es01 bb02,aa09,es02 bb04,aa09,es02 bb06,aa09,es02 bb08,aa09,es02 bbl0, Aa09,es02 bb02,aa09,es03 bb04,aa09,es03 bb06,aa09,es03 bb08,aa09,es03 bbl0,aa09,es03 bb02,aa09,es04 bb04,aa09,es04 bb06,aa09,es04 bb08,aa09,es04 bbl0, Aa09,es04 bb02,aa09,es05 bb04,aa09,es05 bb06,aa09,es05 bb08,aa09,es05 bbl0,aa09,es05 bb02,aa09,es06 bb04,aa09,es06 bb06,aa09,es06 bb08,aa09,es0 6 bbl0,aa09,es06 bb02,aa09,es07 bb04,aa09,es07 bb06,aa09,es07 bb08,aa09,es07 bbl0,aa09,es07 bb02,aa09,es08 bb04,aa09,es08 bb06,aa09,es08 bb08,aa09, Es08 bbl0,aa09,es08 bb02,aa09,es09 bb04,aa09,es09 bb06,aa09,es09 bb08,aa09,es09 bbl0,aa09,es09 bb02,aa09,esl0 bb04,aa09,esl0 bb06,aa09,esl0 bb08,aa09, Esl0 bbl0,aa09,esl0 bb02,aa09,esll bb04,aa09,esll bb06,aa09,esll bb08,aa09,esll bbl0,aa09,esll bb02,aa09,esl2 bb04,aa09,esl2 bb06,aa09,esl2 bb085aa09,esl2 bbl0 ,aa09,esl2 bb02,aal0,es01 bb04,aal0,es01 bb06,aal0,es01 bb08,aal0,es01 bbl0,aal0,es01 bb02,aal0,es02 bb04,aal0,es02 bb06,aal0,es02 bb08,aal0,es02 bbl0 ,aal0,es02 bb02,aal0,es03 bb04,aal0,es03 bb06,aal0,es03 bb08,aal0,es03 bbl0,aal0,es03 bb02,aal0,es04 bb04,aal0,es04 bb06,aal0,es04 bb08,aal0,es04 bbl0 ,aal0,es04 bb02,aal0,es05 bb04,aal0,es05 bb06,aal0,es05 bb08,aal0,es05 bbl0,aal0,es05 bb02,aal0,es06 bb04,aal0,es06 bb06 Aal0,es06 bb08,aal0,es06 bbl0,aal0,es06 bb02,aal0,es07 bb04,aal0,es07 bb06,aal0,es07 bb08,aal0,es07 bbl0,aal0,es07 bb02,aal0,es08 bb04,aal0,es08 bb06, Aal0,es08 bb08,aal0,es08 bbl0,aal0,es08 bb02,aal0,es09 bb04,aal0,es09 bb06,aal0,es09 bb08,aal0,es09 bbl0,aal0,es09 bb02,aal0,esl0 bb04,aal0,esl0 bb06, Aal0, esl0 bb08, aal0, esl0 bbl0, aal0, esl0 bb02, aal0, esll bb04, aal0, esll bb06, aal0, esll bb08, aal0, esll bbl0, aal0, esll bb02, aal0, esl2 bb04, aal0, esl2 bb06, Aal0, esl2 bb08, aal0, esl2 bbl0, aal0, esl2 Table 2

bbOl -Kw> bb02 bb03 bb04 cr bb05 Cl bb06 bb07 bb08 , servant \ bb09 Op bblO 158865.doc -50-

201217392

Table 4 esOl Ra = thiol es02 Ra = ethyl es03 Ra = isopropyl es04 Ra = propyl es05 Ra = cyclohexyl es06 R « = cyclopentyl es07 R « = cyclobutyl es08 Ra = cyclopropyl es09 Ra = benzoinyl esll R «= neopentyl eslO Ra = tert-butyl esl2 R < x = hydrogen In some embodiments, R3a, R3b, R4, R5 and R9 are in any of the embodiments described in Table 1. They can all be hydrogen. In some embodiments, at least one of R6 and R7 can be OH in any of the embodiments described in Table 1. In some embodiments, R8 can be a CN6 alkyl group in any of the embodiments described in Table 1. In some embodiments, B1 can be adenine, guanine, uracil, thymine or cystine in any of the embodiments described in Table 1. In some embodiments, R3a, R3b, R4, R5, R6, R7, R8, R9&B1 can be the group provided for formula (Id) in any of the examples described in Table J. 158865.doc -51 - 201217392 Examples of compounds of formula (i) include, but are not limited to, the following:

158865.doc -52 201217392

158865.doc -53- 201217392

158865.doc -54- 201217392 OCH*

158865.doc -55 201217392

and

Ό Ο

Other examples of compounds of formula (I) include, but are not limited to, the following: 158865.doc 56- 201217392

In some embodiments, the compound of formula (i) can be as follows: 158865.doc 57- 201217392

Other examples of compounds of formula (i) include the following:

158865.doc • 58 · 201217392 HO-P—Ο—一Ο—ί

Ο

I

I II \ ΜΗ

Hcf

OH ΟΗ F

and

In some embodiments, the charge on the neutralized phosphorothioate group can be made more by comparing the compound to a thionucleotide having a similar structure having one or more charges present on the phosphate group. Lipidity contributes to the penetration of the compound of formula (1), including the compound of formula (Ια), through the cell membrane. The group attached to the thioscale ester can be easily removed by esterases, proteases or other enzymes after absorption and uptake into the cells. In some embodiments, the group attached to the phosphorothioate can be removed by simple hydrolysis. Inside the cell, the thiomonophosphate thus released can then be metabolized by the cellular enzyme to a thiodiphosphate or active thiotriphosphate. In some embodiments, the thiomonophosphate of a compound of formula (1) or a pharmaceutically acceptable salt thereof can undergo stereoselective phosphorylation. For example, the thiomonophosphate of the compound of formula (I) (including the compound of formula (Ια)) can be phosphorylated to obtain α•thiodiphosphate and/or α•thiotriphosphate 158865.doc • 59· 201217392, which can be enriched to the (and) or (S)-type diastereomers of the 5·-0-phosphorus atom. For example, the α-thiodiphosphate and/or α-thiotriphosphate compound can be compared to one of the 5'-0-scale atoms (and) and ("S) configuration. 5·-0-phosphorus atom (or) or (the amount of the other in the magic configuration > 5〇%, 275%, >90%, 295% or > 99% of the amount exists. In some In embodiments, phosphorylation of a compound of formula (I) or a pharmaceutically acceptable salt thereof can form a compound having a (Λ) configuration at a 5 _ 构-constituting atom. In some embodiments, a compound of formula (I) or Its pharmaceutically acceptable salt phosphorylation can form a compound having a (*s) configuration at the 5,_〇_ phosphorus atom. In some embodiments, a compound of formula (I) (including a compound of formula (Ια)) Or a pharmaceutically acceptable salt thereof can serve as a chain terminator for HCV replication. For example, incorporation of a compound of formula (I) containing a moiety at the 2' carbon position can terminate the RNA chain of HCV further. 'When Rs is a non-hydrogen group selected from the group consisting of halogen, azido, cyano, optionally substituted Cw alkyl, -〇rw and -〇C(=〇)R17, the compound of formula (I) may contain 2. Carbon Modifications. In some embodiments, a compound of Formula (I), including a compound of formula (Ια), or a pharmaceutically acceptable salt thereof, may have enhanced metabolism and/or plasma stability. In some embodiments The compound of the formula (1) (including the compound of the formula (Ια)) or a pharmaceutically acceptable salt thereof may have greater hydrolysis resistance and/or greater resistance to enzymatic conversion. For example, compared to the structure a compound of the formula (I) or a pharmaceutically acceptable salt thereof which has the same but a 5' carbon phosphate group attached to the ribose ring, may have enhanced metabolic stability and enhanced plasma stability. Large hydrolysis resistance and/or may have greater resistance to enzymatic conversion. In some embodiments, compounds of formula (1) (including formula (Ια) 158865.doc -60·

201217392 Compound) or a pharmaceutically acceptable salt thereof may have improved properties. In a previous study, the replacement of sulfur with oxygen on the α•phosphate sulphate of phosphatidyl citrate resulted in a decrease in potency of kata_ times more than that of menkatachaiam, EUropean Journal 吋Medicinai Q(10)(eight)^ 39··665- 683. A non-limiting list of exemplary characteristics includes, but is not limited to, prolonged biological half-life, increased bioavailability, enhanced potency, sustained in vivo response, prolonged dosing interval, reduced dosing, reduced cytotoxicity, and treatment of disease conditions. Reduced need, reduced viral load, reduced seroconversion (ie, the virus becomes undetectable in the patient's serum), increased sustained viral response, reduced morbidity or mortality in clinical outcomes, improved individual compliance, Conditions such as liver fibrosis, cirrhosis and/or liver cancer reduce 'and compatibility with other drugs. In some embodiments, the biological half-life of the compound of formula (1) or a pharmaceutically acceptable salt thereof is longer than 24 hours. In some embodiments, the biological half-life of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is in the range of from about 40 hours to about 46 hours. In some embodiments, the biological half-life of the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be longer than a compound having a phosphate group attached to the 5, carboxy sugar ring of the ribose ring (eg, structurally identical but having a linkage 5 to the ribose ring, a phosphate phosphate based compound). In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, may have a more potent antiviral activity (e.g. '<><5> in HCV replicon assay) than the current standard of care. The synthesis of a compound of formula (I) (including a compound of formula (Ια)) and the general synthetic route for the preparation of a compound of formula (I) in various ways and for the initiation of the synthesis of formula (1) 158865.doc 201217392 σ Some examples of materials are shown in the Schemes and are described herein. The exemplifications are shown and described herein, and are not intended to limit the scope of the claims. Those skilled in the art will recognize modifications to the disclosed compositions based on the disclosure herein and substitute alternatives, all of which are within the scope of the patent application. Process 1

R3A HO—i^R3B B 1A

R2〇—P— (A) s

Cl

One method of forming a compound of formula (I) is shown in Scheme i. In the scheme i, 'R3A, R3B, R4A, R5A, r6A, r7A, r8A, r9a and β1Α may be as R3a, R3b, R4, R5, r6, r7, r8, R9 as described herein for formula (I) and B1 is the same; and R1 and R2 may be the same as described herein for formula (1). As shown in Scheme 1, a compound of formula (A) can be reacted with a compound having the formula R2〇_p(=s)(R"_cl to form a compound of formula (I). One or more can be used to reduce by-product formation. A suitable protecting group is attached to one or more groups of the pentose ring. For example, if the ampule 6 and/or R7A is a hydroxy group, a suitable protecting group such as a triaryl fluorenyl group and/or a decyl group may be used. Protecting a hydroxyl group. Examples of triarylmethyl groups include, but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4·-dimethoxytrityl (DMTr), 4,4,,4·,-Trimethoxytrityl (TMTr), 4,4·,4"-Find (Benzene I58865.doc •62- 201217392 methoxyl)trityl (TBTr) , 4,4,,4"_(4,5-dichloro-o-phenylenedimino)trityl (CPTr), 4,4,,4"·ginsyl (acetamidine) Trityl (TLTr), p-large oxime methyl xiaocao phenylmethyl, di-o- yin yin methyl · 1 - naphthylmethyl, p-tolyl diphenylmethyl, 3 (taste Methyl group 4,4·_dimethoxytriphenylmethyl, 9·phenyldibenzophenan-9 base (8), 9 -(p-methoxyphenyl)dibenzopyran_9-yl (indole), 4-methoxyl trityl, 4-hexadecyloxytrityl, 4,4, _Dioctadecyltrityl, 9-(4-octadecyloxyphenyl)dibenzopyran·9-yl, hydrazine, bis, bis(4-methoxyphenyl)- Γ_Μmethyl, 4'4''4"-parade (t-butylphenyl)methyl (TTTr) and M'_di-3,5·hexadienyloxytrityl. Suitable for dreams Examples of the radicals are described herein. Alternatively, R6A and/or R?A may be protected by a single non-pivoling or palmitic protecting group, for example by formation of the ortho-acid, cyclic or cyclic ketal. Protection. Suitable for the original _ including oxymethylene condensate, ethoxymethylene acetal, 2-oxacyclopentylene orthoester, dimethoxymethylene acid vinegar, Oxyethyleneethylene orthoester, ethoxylated ethyl ortho acid S曰, methylene orthoester, benzoate orthoester, anthracene, 2-dimethoxyethylene ortho acid _-methoxybenzylidene acid g; suitable ring-shaped shrinkage includes methylene acetal, ethylene acetal, tert-butylmethylene acetal, 3-(benzophenoxy) a propyl shrink disk, a benzylidene chain, a 3,4. dimethoxybenzylidene group, and a p-ethoxybenzyl acetal acetal; and a suitable cyclic ketal includes 1 Tributylethylene ketal, hydrazine-phenylethyl condensed _, isopropylidene ketal, cyclopentylene ketal, cyclohexylene ketal, cycloheptyl ketal, and methoxybenzene Ethylene ketal. If necessary, one or more suitable protecting groups may be used to protect any -NH and/or NH2 groups present on the β1 Α I58865.doc -63· 201217392. Examples of suitable protecting groups include Sanfang. Alkyl and decyl. Examples of sulfonyl groups include, but are not limited to, trimethyl decyl (TMS), tert-butyl dimethyl decyl (TBDMS), triisopropyl decyl (TIPS), tert-butyl diphenyl a decyl group (TbdPS), a triisopropyl decyloxymethyl group, and a [2-(tridecyl decyl) ethoxy] fluorenyl group. Suitable thiochlorophosphates are commercially available or can be prepared by the synthetic methods described herein. An example of a general structure of a thio gas phosphate is shown in Scheme 1. In some embodiments, the thiophosphorus phosphate can be coupled to a compound of formula (A). In some embodiments, to facilitate coupling, a Gngnard reagent can be used. Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, vaporized alkyl magnesium and alkyl magnesium bromide. In other embodiments, a thioglycol phosphate may be added to the compound of formula (A) using a base. Suitable tests are known to those skilled in the art. Suitable tests are known to those skilled in the art. Examples of bases include, but are not limited to, amine bases such as alkylamines (including single-chamber amines, dialkyl amines, and trialkylamines (e.g., triethylamine)); optionally substituted pyridines (e.g., top three) Pyridine); and optionally substituted imidazole (eg N-methylimidazole). At least one of the fields R and R is optionally substituted c 1 a thiol or optionally substituted -6 haloalkyl, which may be used as known to those skilled in the art. Substituted c丨_6 alkyl or optionally substituted C!·6-dentate alkyl is added to the 5' position. In some embodiments, a hydroxyl group attached to the 5' carbon can be oxidized to an aldehyde. Suitable oxidizing conditions include (i) not limited to) DMSO with an activator (usually a hydrating agent or acid) and an amine base combination, Moffatt oxidation, Sven oxidation such as coffee (10) 丨 (4) and 158865.doc • 64· 201217392 C〇rey-Kim oxidation, and suitable oxidants include (but are not limited to) Dess-Martin periodinane, TPAP/NMO (sorghum acid IV) Propyl ammonium/N-methylmorpholine...oxide), Sven oxidation reagent, PCC (pyridinium chromite) and/or PDC (pyridinium dichromate), Ena, Collin's reagent, Ceric ammonium nitrate (CAN), Na2Cr2〇wX solution, Ag2C03/diatomaceous earth, hot HN〇3 solution of ethylene glycol dimethyl ether, 〇2_pyridine cuci, Pb(OAc)4-° Bisidine and peroxyformamide _NiBr2. The resulting aldehyde compound can be reacted with a Grignard reagent, an organolithium reagent or a trialkylaluminum (e.g., trimethylaluminum) to form a compound of formula (A) wherein at least one of amp 3 and r3b is optionally substituted The Cl.6 alkyl group or, as the case may be, the 2Ci6-dentate alkyl group. The carburetor can be used in the presence of Lewis acid, as appropriate. Suitable Lewis acids are known to those skilled in the art.

As described herein, some are connected together by several groups. Methods known to the skilled artisan In some embodiments, both the scales 6 and R7 may be oxygen atoms and the -〇_C(=0)_〇_ group may be used as is known. For example, a compound of formula (I) wherein R6 and R7 are both hydroxy can be treated with 1,1·-carbonyldiimidazole 158865.doc -65 - 201217392 (CDI). In some embodiments, R6 and/or R7 may be -OC(=C〇R13 and -OC(=0)R15, respectively. Various methods known to those skilled in the art may be used at the 2' position and 3'. Forming -〇C(=0)R13 and -0C(=0)R丨5 groups at position 0 For example, 'available alkanoic anhydride (such as acetic anhydride and propionic anhydride) or alkanoic acid vapor (such as acetam) The compound of the formula (1) wherein both R6 and R7 are a hydroxyl group is treated. If necessary, a catalyst may be used to facilitate the reaction. An example of a suitable catalyst is 4-dimethylaminopyridine (DMAP). Alternatively, an alkanoic acid such as acetic acid may be used. Propionic acid) reacts in the presence of a carbodiimide or a coupling reagent to form -OC(=0)R13 and -〇c(=〇)R15 groups at the 2, position and 3 positions. Examples of carbodiimides Including, but not limited to, N,N'-dicyclohexylcarbodiimide (DCC), hydrazine, hydrazine, -diisopropylcarbodiimide (DIC) and 1-ethyl-3-(3-di Mercaptopropyl propyl) carbodiimide (EDC). As described herein, B1A can include urethanes and/or guanamines. It is known to those skilled in the art to form urethanes on B1A. And/or method of guanamine ❶ in some embodiments In the present invention, ij, carbonyldiimidazole and an alcohol can be used to form an amino decanoic acid I. B 叮 is added to the pentose ring by various methods known to those skilled in the art. In some embodiments, The compound of formula (B) is reacted with a nitrogen-containing test group. In some embodiments, the compound of formula (B), rw, r4a, RR'R, R8A, R9A and B]A may be as herein described for R3a, R3b, RR. , R, R, R9 and B1 are the same as disclosed; and PG1 may be a suitable protecting group. In some embodiments, p(}1 may be p-nitrophenyl fluorenyl. In the embodiment, one or more may be used. A suitable protecting group is attached to any of the pentose rings of 158865.doc 201217392. In some embodiments, any of the thiol-containing groups are protected by a thiol group. Examples of nitrogen-containing assays include Optionally substituted heterocyclic test group, wherein the nitrogen atom (•N) attached to the pentose ring is _NH. If necessary, the n-base may be protected by a suitable protecting group or a plurality of suitable protecting groups. Any -NH and/or NH2 groups present. Suitable protecting groups are described herein. In some embodiments, may be in Lewis acid or 1^ In the presence of 8 beats, a nitrogenous base is added via a coupling reaction. Suitable Lewis acids are known to those skilled in the art. P 2 can be used for irOR2 o=-p 1OR1

(B) A method of preparing a compound of formula (I) wherein r1 is . For example, a thio gas phosphate having the formula (P(=s)cl3) can be converted to a phosphorus reagent having the formula P(=S)LG3, wherein each LG can be an amine-based leaving group. In some embodiments, each lg can be a triazole. A phosphorus reagent having the formula P(=S)LG3 can be reacted with a compound of the formula (1). The β and γ-esterate groups can be added using a suitable pyrophosphorylation reagent. An example of a suitable pyrophosphorylation reagent is hydrogen pyrophosphate (tetrabutylammonium). During the synthesis of any of the compounds described herein, any hydroxyl group attached to the pentose ring may be protected by any one or more suitable protecting groups, if desired, and I58865.doc-67-201217392 at any -NH and/or NH2 Group. Suitable protecting groups are described herein. Those skilled in the art will appreciate that any group of -NH and/or NH2 groups attached to the pentose ring and bia ± can be protected with various protecting groups and any protecting groups present can be exchanged for other protecting groups. The choice of protection base and the father's change are within the skill of the general practitioner. Any protecting group can also be removed by methods known in the art, such as with an acid (e.g., inorganic or organic acid), assay, or fluoride source. Pharmaceutical Compositions Some embodiments described herein relate to pharmaceutical compositions which may comprise a therapeutically effective amount of one or more of the compounds described herein (e.g., a compound of formula (1) or (Ια)) or a pharmaceutically acceptable salt thereof, And a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. In some embodiments, a pharmaceutical composition can include a single diastereomer of a compound of formula (I) or a pharmaceutically acceptable salt thereof (eg, a single diastereomer compared to other diastereomeric The total concentration of isomers is present in the pharmaceutical composition at a concentration greater than 99%). In other embodiments, the pharmaceutical compositions may comprise a mixture of diastereomers of a compound of formula (1) or a pharmaceutically acceptable salt thereof. For example, a pharmaceutical composition can include a concentration relative to the total concentration of other diastereomers > 50%, 260%, 270%, 280%, >9%, 295%, or 298%. A diastereomer. In some embodiments, the pharmaceutical composition comprises a 1:1 mixture of two diastereomers of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The term "pharmaceutical composition" refers to a mixture of one or more of the compounds disclosed herein with other chemical components, such as diluents or carriers. Pharmaceutical Combinations 158865.doc -68 - 201217392 Drug-induced compounds are administered to organisms. The pharmaceutical composition can also be obtained by reacting a compound with an inorganic or organic acid such as hydrochloric acid, hydrobromide k, sulfuric acid, acid, phosphoric acid, decanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid. And water acid. Pharmaceutical compositions are generally suitable for a particular intended route of administration. The term "physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound. "Carrier" as used herein refers to a compound that facilitates the incorporation of a compound into a cell or tissue. By way of example and not limitation, dimethyl hydrazine (DMSO) is a common carrier that aids in the absorption of various organic compounds into individual cells or tissues. As used herein, "diluent" refers to a lack of pharmacological activity in a pharmaceutical composition. Fructus can be a medicinally necessary or desired ingredient. For example, dilution J can be used to increase the quality of the drug for volume that is too small for manufacture and/or administration. It may also be a liquid which dissolves a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is buffered water f/liquid such as, but not limited to, phosphate buffered saline which mimics human blood composition. As used herein, "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide "and: an object with, without limitation, a volume, a slight m, a binding ability, a 'disintegration target', etc." The diluent is an excipient of the type. The pharmaceutical compositions described herein may be administered to a human patient per se, or may be administered to a human in the form of a pharmaceutical composition in admixture with other active ingredients or carriers, diluents, excipients or combinations thereof. patient. Proper formulation 158865.doc -69· 201217392 Depending on the route of administration chosen. Techniques for formulating and administering the compounds described herein are known to those skilled in the art. The pharmaceutical compositions disclosed herein can be made in a manner known per se, for example by conventional mixing, dissolving, granulating, preparing a dragee, water milling, emulsifying, encapsulating, burying or tableting process. In addition, the active ingredient is included in an amount effective to achieve the intended purpose. A wide variety of compounds for use in the pharmaceutical compositions disclosed herein can be provided in the form of a pharmaceutically compatible salt-forming salt. There are a variety of techniques for administering compounds in the art including, but not limited to, oral, rectal, topical, aerosol, injection, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections. 1 intraluminal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. The compound may also be administered in a local rather than systemic manner, e.g., via direct injection of the compound into the site of infection, which is often in the form of a reservoir or sustained release formulation. In addition, the drug delivery system can be administered in the form of a liposome coated with a tissue-specific antibody, for example, in the form of a liposome coated with a tissue-specific antibody. Lipids selectively dry to the organ and are absorbed by the n-nosed. Wenmachi. Alternatively, the package may have one or more unit dosage forms containing the active ingredient in a package or dispensing device. Packaging 2 can be a plastic or plastic box, such as a blister pack. Packing or dispenser w: with instructions for administration. The package or dispenser may also be in the form of a pharmacy and stipulation in accordance with the regulations of the government agency that regulates the manufacture, use or sale of the drug. This reflects the approval of the drug form for the use of the drug. Humans or animals are happy. The notice can be obtained, for example, by the US Food and Drug Administration (US 158865.doc 201217392).

The Food and Drug Administration) approves the label or approved product instructions for prescription drugs. Compositions comprising a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and used to treat the indicated condition. Methods of Use One embodiment disclosed herein relates to a method of treating and/or ameliorating a disease or condition, which can comprise administering to a subject a therapeutically effective amount of one or more compounds described herein (such as a compound of formula (I) (including formula (Ια) a compound) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein. Some embodiments disclosed herein are directed to methods of ameliorating or treating a neoplastic disease - which can include administering to a subject having a neoplastic disorder a therapeutically effective amount of one or more compounds described herein (eg, formula (1) and/or (Ια) A compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein. In an embodiment, the neoplastic disease can be cancer. In some embodiments, the neoplastic disease can be a tumor, such as a solid tumor. In one embodiment, the chelating disease can be leukemia. Exemplary leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (aml), and adolescent bone marrow monocytic leukemia (JMML). Some embodiments disclosed herein are directed to methods of inhibiting tumor growth, which can include administering to a subject having a tumor a therapeutically effective amount of one or more compounds described herein (eg, a compound of Formula (I) and/or (Ια)) or A pharmaceutical composition of one or more of the compounds described herein. Other embodiments disclosed herein are directed to methods of ameliorating or treating a viral infection 'which can include administering a therapeutically effective amount to an individual having a viral infection - or 158865.doc -71 - 201217392 a variety of compounds described herein (eg, Formula (I) And/or (Ια) compound) or a pharmaceutical composition comprising one or more compounds described herein. In one embodiment, the viral infection can be caused by a virus selected from the group consisting of an adenovirus, an Alphaviridae, an Arbovirus, an Astrovirus, a Bunyaviridae, a coronal Coronaviridae, Filoviridae, Flaviviridae, Hepadnaviridae, Herpesviridae, Alphaherpesvirinae, beta cancer Betaherpesvirinae, Gammaherpesvirinae, Norwalk Virus, Astroviridae, Caliciviridae, Orthomyxoviridae, deputy Paramyxoviridae, Paramyxovirus, Rubulavirus, Morbillivirus, Papovaviridae, Parvoviridae, Small RNA Virus (Picornaviridae), Foot-and-mouth Disease Virus (Aphthoviridae), Cardioviridae (Cardioviridae), Enteroviridae (Enter Oviridae), Coxsackie virus, Polio Virus, Rhinoviridae, Phycodnaviridae, Poxviridae, Reoviridae Reoviridae), Rotavirus, Retroviridae, Retrovirus, Immunodeficiency Virus, Platinum Virus, Avian Sarcoma Virus, Rhabdovirus, Rheumatology (Rubiviridae), Physcomitidae 15886S.doc -72- 201217392 (Togaviridae), Arenaviridae and/or Bornaviridae. In some embodiments, the viral infection can be a hepatitis C virus (HCV) infection. In other embodiments, the viral infection can be HIV. Some embodiments disclosed herein are directed to methods for ameliorating and/or treating viral infections, which may comprise sensitizing a virus-infecting cell with an effective amount of one or more of the compounds described herein, or a compound described herein. A salt, or a pharmaceutical composition comprising one or more compounds described herein, or a pharmaceutically acceptable salt thereof, in contact with other embodiments described herein, in relation to the use of one or more compounds described herein, or a compound described herein A salt that is acceptable for the manufacture of a medicament for ameliorating and/or treating a viral infection, the improving and/or treating a viral infection can comprise contacting the virus-infected cell with an effective amount of the compound or compounds. Other embodiments described herein pertain to pharmaceutically acceptable salts of any one or more of the compounds described herein, or a compound described herein, for use in ameliorating and/or treating a viral infection, the improvement and/or treatment of a viral infection system This is achieved by contacting the virus-infected cells with the active or such compounds. In some embodiments, the compound can be a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound may be a monophosphate, a diphosphate, and/or a triphosphate of a compound of formula (1) and/or (Ια), or a pharmaceutically acceptable salt thereof. In some embodiments, the virus can be an HCv virus. Some embodiments disclosed herein are directed to methods of inhibiting viral replication, which can include, or include, a virus-infecting cell with an effective amount of one or more of the compounds described herein or a pharmaceutically acceptable salt of a compound described herein. 158865.doc • 73· 201217392 A pharmaceutical composition of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, is contacted. Other embodiments described herein are directed to the use of one or more compounds described herein, or a pharmaceutically acceptable salt of a compound described herein, to manufacture a medicament for inhibiting viral replication, which may include viral infection. The cells are contacted with an effective amount of the compound or compounds. Other embodiments described herein pertain to a compound described herein, or a pharmaceutically acceptable salt of a compound described herein, which is useful for inhibiting viral replication by sensitizing virally infected cells with an effective amount thereof. The or the compounds are contacted to achieve. In some embodiments, the compound can be a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound can be a monophosphate, diphosphate, and/or triphosphate of a compound of formula (I) and/or (Ια), or a pharmaceutically acceptable salt thereof. In some embodiments, the virus can be an HCV virus. HCV is an enveloped positive-stranded RNA virus in the yellow fever virus family. There are various HCV non-structural proteins such as NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B. NS5B is an RNA-dependent RNA polymerase involved in HCV RNA replication. Some embodiments described herein are directed to methods of inhibiting NS5B polymerase activity, which can include culturing a cell (eg, a cell that infects HCV) with an effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable compound thereof Accept the salt contact. Some embodiments described herein are directed to methods of inhibiting NS5B polymerase activity, which can comprise administering to a cell (eg, a cell infected with HCV) an effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable compound thereof Accept the salt. In some embodiments, a compound of formula (I), including a compound of formula (Ια), or a pharmaceutically acceptable salt thereof, 158865.doc-74·201217392, inhibits RNA-dependent RNA polymerase. In some embodiments, a compound of formula (I), including a compound of formula (Ια), or a pharmaceutically acceptable salt thereof, inhibits HCV polymerase (e.g., NS5B polymerase). Some embodiments described herein are directed to a method of treating an HCV infection in an individual having an HCV infection, which can comprise administering to the individual an effective amount of a compound of formula (1) and/or (Ια) or a pharmaceutically acceptable salt thereof. Or a pharmaceutical composition comprising an effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof. Some embodiments described herein are directed to methods of treating a condition selected from the group consisting of liver fibrosis, cirrhosis, and liver cancer in an individual having one or more of the following liver conditions, which can include administering to the individual an effective amount of a compound described herein Or a pharmaceutical composition (for example, a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof). One of the causes of liver fibrosis, cirrhosis and/or liver cancer can be HCv infection. Some embodiments described herein are directed to methods of increasing liver function in an individual having an HCV infection, which can comprise administering to the individual an effective amount of a compound or pharmaceutical composition described herein (eg, formula (1) and/or (Ια). a compound or a pharmaceutically acceptable salt thereof). Also contemplated is a method of reducing or eliminating liver damage caused by a virus in an individual having an Hcv infection by administering to the individual an effective amount of a compound or pharmaceutical composition described herein (eg, formula (1) and/or (Ια) The compound or a pharmaceutically acceptable salt thereof is used. In one embodiment, the method comprises slowing or halting progression of liver disease. In another embodiment, the course of the disease is reversed and liver function is expected to be maintained or improved. There are a variety of HCV genotypes, and there are multiple subtypes within each genotype. For example, 5, it is known that there are u species (numbered as 丨 to 丨^ major genotypes, although others divide the genotype into six major gene Μ. These genotypes 158865.doc •75· 201217392 are further subdivided Each subtype (la_lc; 2a2c; 3a3b; 4a4e丨5a; 6a '7a-7b; 8a_8b; 9a; 1〇a; and Ua). In some embodiments, an effective amount of formula (I) and/or (Ια) The compound or a pharmaceutically acceptable or a pharmaceutical composition thereof having an effective amount of the formula (1) and/or (1〇0 compound or a pharmaceutically acceptable salt thereof) is effective for treating at least one Hcy genotype. In some embodiments, a compound described herein (eg, a compound of formula (1) and/or (10) or a pharmaceutically acceptable salt thereof) is effective to treat all η HCV genotypes. In some embodiments, the compounds described herein For example, the compound of the formula (1) and/or (10) or a pharmaceutically acceptable salt thereof can effectively treat three or more, five or more, seven or seven species of ±, nine or more. HCV genotype. In some embodiments, a compound of formula (1) and / or (d) or a pharmaceutically acceptable salt phase thereof More effective for a variety of genotypes in terms of care standards. In some implementations, a compound of formula (1) and/or (10) or a pharmaceutically acceptable salt thereof is more effective against a particular HCV genotype than the standard of care ( For example, genotypes i, 2, 3, 4, 5, and (6)). Various examples of well-known methods known to those skilled in the art for determining the effectiveness of methods for treating HCV money include, but are not limited to, reduced viral load. Reduced viral replication, seroconversion (the virus is not in the patient's serum), time-reducing effect, sustained viral response to therapy, clinical outcomes = decreased morbidity or mortality, decreased rate of liver function reduction; liver function: Steady liver function improvement, one or more markers of liver dysfunction minus 'including alanine transaminase, aspartate transaminase, total bilirubin, bound bilirubin, Y glutamine thiol Peptidase; and/or other indications of disease response. Similarly, a compound or pharmaceutical composition described herein (eg, formula 158865.doc •76-201217392 (I) and/or (Ια) compound or its medicinal Acceptable salt) Therapy can reduce the incidence of liver cancer in HCV patients. In some embodiments, an effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof is effective to reduce viral titer to undetectable The level of measurement is reduced, for example, to about 1 to about 5, about 5 to about 1000, or about 1 to about 5 genome copies per milliliter of serum. In some implementations. In an embodiment, the effective amount of the compound of the formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof is effective to make the viral load comparable to the administration of the compound of the formula (1) and/or (Ια) or its medicinal The amount of viral load before the acceptable salt is reduced. For example, wherein the viral load is measured prior to administration of the compound of formula (1) and/or (Ια) or a pharmaceutically acceptable salt thereof, and the compound of formula (1) and/or (Ια) or its pharmacology is used. The viral load is measured after the acceptable salt is completed (eg, 1 month after completion). In some embodiments, an effective amount of a compound of formula (I) and/or (Ια), or a pharmaceutically acceptable salt thereof, can be effective to reduce viral load to less than about one genome copy per milliliter of serum. the amount. In some embodiments, an effective amount of a compound of formula (1) and/or (Ια) or a pharmaceutically acceptable salt thereof is effective to render the virus titer in an individual clear compared to the formula (1) and/or ( The viral load prior to the Ια) compound or a pharmaceutically acceptable salt thereof is such that a reduction in the following range is achieved: about 1.5-1 〇§ to about 2.5-1 邛 reduction, about 3_1 〇§ to about 4_1 〇§ reduction or More than about 51 calls are lowered. For example, the viral load can be measured prior to administration of a compound of formula (1) and/or (Ια) or a pharmaceutically acceptable salt thereof, and using a compound of formula (1) and/or (chemical) or S f § The viral load is measured after the acceptable salt has completed the treatment regimen (eg, '1 month after completion'). 158865.doc •77· 201217392 In some embodiments, the 'formula (i) and/or (Ια) compound or a pharmaceutically acceptable salt thereof can be determined as after completion of the treatment regimen (eg, one month after completion) Reducing the replication of HCV in an individual by at least j, 2, 3, 4, 5, 1 , 15, 20, 25, 50, 75, 1 相对 relative to the pre-treatment level 〇 times or 丨 00 times or more. In some embodiments, the compound of formula (1) and/or (Ια), or a pharmaceutically acceptable salt thereof, reduces the replication of HCv by from about 2 fold to about 5 fold, from about 1 to about 2 fold, relative to the pre-treatment level. From about 15 times to about 40 times or from about 50 times to about 100 times. In some embodiments, a compound of Formula (I) and/or (Ια), or a pharmaceutically acceptable salt thereof, causes HCV replication to produce a reduction in the following range: interference with polyethylene glycolation administered by the care standard Hcv replication achieved by a combination of cytosine and ribavirin reduces HCV replication to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 log to 3 log, 3 log to 3.5 log or 3.5 log to 4 log A reduction, or a reduction achieved after six months of standard care with ribavirin and pegylated interferon, can be achieved in a shorter period of time, for example within one month, two months or two months. The reduction in care achieved by standard therapy is the same reduction. In some embodiments, an effective amount of a compound of formula (1) and/or (Ια), or a pharmaceutically acceptable salt thereof, is an amount effective to achieve a sustained viral response, such as undetectable or in the serum of an individual. HCV RNA that is substantially unmeasurable (eg, less than about 5, less than about, less than about 200, or less than about 1 genome copy per milliliter of serum) and maintained at least about after stopping therapy One month, at least about two months, at least =, 'J two months, at least about four months, at least about five months, or at least about six months. 158865.doc -78- 201217392 In some embodiments, a therapeutically effective amount of a compound of formula (I) and/or (Ια) or a pharmaceutically acceptable salt thereof provides a liver fibrosis marker content as compared to no The amount of the in vivo marker of the treated individual or placebo treated subject is reduced by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35% 'at least about 40%, at least about 45°. /. At least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80% or more. Methods for measuring serum markers are known to those skilled in the art and include immunological methods using antibodies specific for a given serum marker, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay. And similar methods. A non-limiting list of examples of markers includes measuring serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma glutamate using known methods. The content of transpeptidase (GGT) and total bilirubin (TBIL). In general, the ALT content is less than about 45 IU/L (International Units/Liter), the AST is in the range of 10 to 34 111/1^, the VIII is in the range of 44-147 111/[, and the 00 is at 0- It is considered normal within the range of 51 IU/L and TBIL in the range of 0.3-1.9 mg/dL. In some embodiments, an effective amount of a compound of formula (I) and/or (Ια) is an amount effective to reduce the levels of ALT, AST, ALP, GGT, and/or TBIL to a level that is considered normal. Individuals clinically diagnosed with HCV infection include "naive" individuals (eg, individuals who have not previously been treated for HCV, particularly those who have not previously received IFN-[alpha] and/or viral saliva based therapy) and Individuals who were previously ineffective against HCV treatment ("treatment ineffective" individuals). Ineffective individuals included "non-responders" (ie, individuals who had previously had no significant or sufficient reduction in HCV titers (^0.5 log IU/mL) for HCV 158865.doc -79·201217392, the previous treatment for HCV For example, previous IFN-α monotherapy, combination therapy with previous IFN-a and viral sputum, or combination therapy with previously PEGylated IFN-a and viral sputum; and "relapsed" (ie previously treated for HCV, eg accepted Previous IFN-a monotherapy, combination therapy with previous IFN-a and ribavirin, or previously PEGylated IFN-a in combination with ribavirin, and individuals with reduced HCV titers and subsequent elevation). In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a treatment-ineffective individual having HCV. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a non-responsive individual having HCV. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a relapsed subject having HCV. After a certain period of time, the infectious agent may develop resistance to one or more therapeutic agents. The term "resistance" as used herein refers to a strain of a virus that exhibits a delayed, attenuated, and/or ineffective response to a therapeutic agent. For example, after treatment with an antiviral agent, the viral load of an individual infected with a resistant virus may be reduced to a lesser extent than the amount of viral load exhibited by an individual infected with a non-resistant viral strain. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to an individual infected with an HCV strain that is resistant to one or more different anti-HCV agents. In some embodiments, when a patient is treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof, the production of a HCV strain can be delayed compared to the production of a HCV strain resistant to other HCV drugs. . In some embodiments, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered to an individual who is contraindicated against other anti-HCV drugs. For example, 158865.doc -80· 201217392, individuals with hemoglobin (such as severe anemia) and blood with current therapy = cell-specific individuals in combination with pegylated interferon alpha and ribavirin have J It: In some embodiments, it may be sensitive to interferon or virus (tetra): a compound of formula (I) or a pharmaceutically acceptable salt thereof. - Some individuals who are treated for HCV experience a viral load recovery. As used herein, the term “recovery of viral load” is biased above the lowest point before the end of treatment, with an increase of log5 log IU/mL, with the lowest point being 20.5 log iu/mL from baseline. In some embodiments, a compound of formula (1) or a pharmaceutically acceptable salt thereof can be administered to an individual experiencing a disease #load recovery' or can prevent the viral load from rising when used to treat an individual. The standard of care for the treatment of HCV is associated with several side effects (adverse events). In some embodiments, a compound of formula (I), including a compound of formula (ια), or a pharmaceutically acceptable salt thereof, can be reduced in HCV patients treated with ribavirin and pegylated interferon according to care standards The number and/or severity of side effects observed. Examples of side effects include (but are not limited to) fever, discomfort, tachycardia, chills, headache, joint pain, muscle pain, fatigue, apathy, loss of appetite, nausea, beta vomiting, cognitive changes, weakness, lethargy, Lack of initiative, irritability, confusion, depression, major depression, suicidal ideation, anemia, low white blood cell count and hair thinning. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be provided to an individual who discontinues HCV therapy by one or more adverse effects or side effects associated with one or more other HCV agents. Table 5 provides some examples of the quasi-comparison of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compliant label 158865.doc • 81 - 201217392. Examples include the following: In some embodiments, the percentage of non-responders receiving a compound of formula (I) or a pharmaceutically acceptable salt thereof is 10% less than the percentage of non-responders receiving care standards; The number of side effects experienced by an individual receiving a compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 10% to about 30% less than the number of side effects experienced by an individual receiving the care standard; and in some embodiments The side effects experienced by an individual receiving a compound of formula (I) or a pharmaceutically acceptable salt thereof (such as a side effect described herein) are 25% less severe than the same side effects experienced by an individual receiving the standard of care. . Methods for quantifying the severity of side effects are known to those skilled in the art. Table 5 Percentage of Non-Responders Percentage of Responders Percentage of Responsiveness of Virus Load Recovery Number of Side Effects Seriously Reduced by 10% Less 10% Less 10% Less 10% Less 10% Low 10〇/^ ~~ Less 25% Less 25% less 25% less 25% less 25% ^&25% less 40% less 40% less 40°/minimum 40% less 40% lower 40〇/〇 less 50% less 50% less 50% less 50% 50% less 500^ less 60% less 60% less 60% less 60% less 60% <6.60% · less 70% less 70% less 70% less 70% less 70% mo%~ less 80% less 80% 80% less 80% less 80% Έδό% 90% less 90% less 90% less 90% less 90% 7&90% less about 10% at least about 10% at least about 10% less than about 10% less than about 10% From about 10% to about 30%, from about 30% to about 30%, about 30%, about 30%, about 30%, about 20% less, at least about 20%, at least about 20%, less than about 20%, at least about 20%, and about 20% lower. Up to about 50% about 50% to about 50% about 50% about 50% about 50% less about 30% at least about 30% at least about 30% less about 30% at least about 30% to about 30% to about 70% lower 70% to about 70% about 70% about 70% about 70% less about 20% at least about 20% at least about 20% less than about 20% at least about 20% to as low as about 20c/〇 to about 80% about 80% to about 80% about 80% about 80% about 80 % Other embodiments disclosed herein are directed to methods of ameliorating or treating a parasitic disease, which can include administering one of a therapeutically effective amount to an individual having a parasitic disease or 158,865.doc -82 - 201217392 of a plurality of compounds described herein (eg, A compound of formula (I) and/or (Ια), or a pharmaceutical composition comprising one or more compounds described herein. In one embodiment, the parasitic disease can be Chagas' disease. "Individual" as used herein refers to an animal that is a subject of treatment, observation or experimentation. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and especially mammals. "Making animals" include, without limitation, mice, rats, rabbits, guinea pigs, dogs, sheep, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and baboons, and especially humans. In some embodiments, the individual is a human. The term "treatment" or "therapy" as used herein does not necessarily mean that the disease or condition is generally cured or removed. Any reduction in any unnecessary signs or symptoms of a disease or condition can be considered as a treatment and/or therapy to any degree. Further treatment may include the effect of possibly aggravating the overall well-being or appearance of the patient. The term "therapeutically effective amount" is used to indicate the amount of a biological or pharmaceutical reaction of an active compound or pharmaceutical agent as indicated. For example, a therapeutically effective amount of a compound can be an amount required to prevent, alleviate or ameliorate the symptoms of the disease or prolong the survival of the individual being treated. This reaction can occur in tissues, systems, animals or humans' and includes alleviation of signs or symptoms of the disease being treated. In view of the disclosure provided herein, the determination of a therapeutically effective amount should be well within the capabilities of those skilled in the art. The therapeutically effective amount required for the compounds disclosed herein will depend on the route of administration, the type of animal (including human) being treated, and the physical characteristics of the particular animal in question. The dosage may be adapted to achieve the desired effect, but will depend on such factors as body weight, diet, concomitant medications, and other factors recognized by those skilled in the art of 158865.doc • 83· 201217392. As will be readily apparent to those skilled in the art, the amount of in vivo pharmaceutical agent and the particular mode of administration will depend on the age, weight, severity of the disease, the mammalian species being treated, the particular compound employed, and the use of such compounds. It varies depending on the specific use. The effective dosage of the dose required to achieve the desired result can be determined by conventional methods (e.g., human clinical trials and in vitro studies) by those skilled in the art. The dosage range can be broad, depending on the desired effect and the therapeutic indication. Alternatively, the dosage can be calculated based on the body surface area of the patient and based on the body surface area of the patient' as understood by those skilled in the art. Although the exact dose should be determined on a drug-by-drug basis, in some cases an overview of the dose can be made. The dosage regimen for use in an adult patient can be, for example, an oral dose of from 0.01 mg to 3 mg, preferably from i mg to 700 mg, for example from 5 mg to 200 mg of each active ingredient. The dose may be administered in a single administration or in two or more than one or more times in one or more days, depending on the individual needs. In some embodiments, the compound will be administered for a period of sustained therapy' such as one week or more than one week, or months or years. In some embodiments, the compound of formula (I) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof may be administered at a frequency less than the frequency of administration of the agent within the standard of care. In some embodiments, a compound of formula (I) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can be administered once per hydrazine. For example, a compound of formula (1) or a pharmaceutically acceptable salt thereof can be administered to an individual having an HCv infection once daily. In some embodiments, the total time of treatment with a compound of formula (I) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof may be 158865.doc -84·201217392 shorter than treatment with care standards The total time of the program. Where the human dose of the compound has been established for at least some condition, 'the same dose can be used, or about 0.1% to 500% of the established human dose is used, preferably about 25% to 250% of the dose. . In the absence of a human dose, 'as found in the newly discovered pharmaceutical composition, the ed50 or id50 value defined by the Institute for Toxicity Research and Efficacy of Animals or other suitable values obtained by in vitro or in vivo studies can be used freely. Infer the appropriate human dose. In the case of administration of a pharmaceutically acceptable salt, the dosage can be calculated as the free base » ten. As is known to those skilled in the art, in certain instances, it may be desirable to administer a compound that is not disclosed herein in excess of or even in excess of the above preferred dosage range for effective and aggressive treatment. Sexual disease or infection. The dosage and time interval can be adjusted individually to provide an active portion of the plasma level sufficient to maintain a modulating effect or a minimum effective concentration (MEC). The MEC of each compound is different, but can be estimated from in vitro data. The dosage required to achieve MEC will depend on individual characteristics and route of administration. However, HpLC assays or bioassays can be used to determine plasma concentrations. The dosing interval can also be determined using the mec value. The composition should be administered using a regimen that maintains plasma levels above the MEC over a period of from 1% to 9% (preferably from 3% to 9% and optimally from 50% to 90%). In the case of topical administration or selective absorption, the effective local concentration of the drug may be independent of plasma concentration. It should be noted that the attending physician should know how and when to terminate, interrupt or modulate the administration due to toxicity or organ dysfunction. On the contrary, the attending physician should also be aware of 158865.doc •85_ 201217392 If the clinical response is inadequate, the treatment will be at a higher level (avoiding toxicity). The amount of the dose administered in the management of the relevant condition will vary with the condition being treated. The severity and the route of administration vary. The severity of the condition can be assessed, for example, to some extent by standard prognostic assessment methods. In addition, the dosage and perhaps the frequency of administration will vary depending on the age, weight and response of the individual patient. A protocol similar to that discussed above can be used in veterinary medicine. The efficacy and toxicity of the compounds disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing certain chemical moieties can be established by determining the in vitro toxicity against a cell line, such as a mammal and preferably a human cell line. The results of such studies often predict toxicity to animals, such as mammals, or more particularly humans. Alternatively, known methods can be used to determine the toxicity of a particular compound to an animal model, such as a mouse, mouse, rabbit or monkey. Several recognized methods, such as in vitro methods, animal models, or human clinical trials, can be used to establish the efficacy of a particular compound. When selecting a model is more effective, the skilled artisan can select the appropriate model, dosage, route of administration, and/or regimen based on the state of the art. Combination Therapy In some embodiments, a compound disclosed herein (such as a compound of formula (1) (including a compound of formula (Ια))), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein, may be Or a variety of them: the use of the drug two. Examples of other agents which may be used in combination with a compound of formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof include, but are not limited to, currently used in therapy (10) The agent in the conventional care standard, the protease inhibitor, HCV polymerase 158865.doc -86 - 201217392 inhibitor, NS5 A inhibitor, other antiviral compound, compound of formula (AA) (including compound of formula (AA) Monophosphate, diphosphate and/or triphosphate, pharmaceutically acceptable salts, and may include a compound of formula (AA), a monophosphate, a diphosphate thereof and/or a triphosphate or a pharmaceutical thereof a pharmaceutical composition of an acceptable salt), a compound of formula (BB) (including a pharmaceutically acceptable salt, and a pharmaceutical composition which may comprise a compound of formula (BB) or a pharmaceutically acceptable salt thereof), DD) a compound (including a pharmaceutically acceptable salt and a pharmaceutical composition which may comprise a compound of formula (DD) or a pharmaceutically acceptable salt thereof), and/or combinations thereof. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be combined with one or both of the compounds described herein. Species, three or more other agents are used together. A non-limiting list of examples of combinations of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, is provided in Tables A, B. , C and D. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, is currently used in the context of conventional care standards The agents in the therapy are used in combination. For example, to treat HCV, the compounds disclosed herein can be combined with pegylated interferon-a-2a (trade name: PEGASYS®) and ribavirin, or pegylated interferon-a-2b (trade name) : PEG-INTRON®) and ribavirin are used in combination. As another example, the compounds disclosed herein can be used in combination with oseltamivir (TAMIFLU®) or zanamivin (RELENZA®) for the treatment of influenza infection. 158865.doc • 87 - 201217392 In some embodiments, a compound of formula (i) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, may be substituted Currently used in conventional care standard therapy. For example, for the treatment of HCV, a virus of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in place of the virus. sit. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be associated with an interferon (such as polyethylene) Alcoholized interferon) is used in combination. Examples of suitable interferons include, but are not limited to, pegylated interferon-a-2a (trade name: PEGASYS®), pegylated interferon-a-2b (trade name: PEG-INTRON®), complex Interferon (interferon alfacon)-l (trade name: INFERGEN®), pegylated interferon λ and/or combinations thereof. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be used in combination with an HCV protease inhibitor. A non-limiting list of exemplary HCV protease inhibitors includes the following: VX-950 (TELAPREVIR®), MK-5172, ABT-450, BILN-2061, BI-201335, BMS-650032, SCH 503034 (BOCEPREVIR®), GS -9256, GS-9451, IDX-320, ACH-1625, ACH-2684, TMC-435, ITMN-191 (DANOPREVIR®) and/or combinations thereof. A non-limiting list of exemplary HCV protease inhibitors includes the compounds numbered 1001-1014 in Figure 2. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical group comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, 158865.doc-88

The 201217392 compound can be used in combination with an HCV polymerase inhibitor. In some embodiments, the HCV polymerase inhibitor can be a nucleoside inhibitor. In other embodiments, the HCV polymerase inhibitor can be a non-nucleoside inhibitor. Examples of suitable nucleoside inhibitors include, but are not limited to, RG7128, PSI-7851, PSI-7977, INX-184, PSI-35293 8, PSI-661, 4'-pyrylic uridine (including 4,- Known prodrugs of azidouridine, GS-6620, IDX-184, and TMC649128, and/or combinations thereof. A non-limiting list of exemplary nucleoside inhibitors includes the compound numbered 2001-2010 in Figure 3. Examples of suitable non-nucleoside inhibitors include, but are not limited to, technetium-333, ANA-598, VX-222, HCV-796, BI-207127, GS-9190, PF-00868554 (FILIBUVIR®), VX-497, and / or a combination thereof. A non-limiting list of exemplary non-nucleoside inhibitors includes the compounds numbered 3001-3008 in Figure 4. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be used in combination with an NS5A inhibitor. A non-limiting list of exemplary NS5A inhibitors includes BMS-790052, PPI-461, ACH-2928, GS-5885, BMS-824393, and/or combinations thereof. A non-limiting list of exemplary NS5A inhibitors includes the compounds numbered 4001-4005 in Figure 5. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, can be used in combination with other antiviral compounds. Examples of other antiviral compounds include, but are not limited to, Debio-025, MIR-122, and/or combinations thereof. A non-limiting list of exemplary other antiviral compounds includes the compound numbered 5001-5002 in Figure 6. 158865.doc -89 - 201217392 In some embodiments, a compound of formula (i) or a pharmaceutically acceptable compound thereof A salt or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a compound of formula (AA), a monophosphate, a diphosphate thereof and/or a triphosphate, or a pharmaceutically acceptable thereof An acceptable salt, or a pharmaceutical composition comprising a compound of formula (AA), a monophosphate, a diphosphate thereof and/or a triphosphate, or a pharmaceutically acceptable salt thereof, is used in combination (see September 22, 2010) U.S. Provisional Application No. 61/385,425, filed on Jan. 27, the entire filing date of

rAA5 rM6 Formula (AA) wherein BAA1 can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base having a protected amine group; RAA1 can be an optionally substituted N-linked amine group An acid or optionally substituted N-linked amino acid vinegar derivative; RAA2 may be selected from optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic; 11^33 And RAA3b may be independently selected from hydrogen, optionally substituted C1 -6 alkyl, optionally substituted c2 6 dilute, optionally substituted CM alkynyl, optionally substituted c, · 6 _ And an aryl group (C!.6 alkyl), the restriction is that at least one of RAA3a & RAA3b is not hydrogen; or RAA3a may form a group selected from RAA3b-B selected from: CM naphthenic optionally substituted Substituted, as appropriate (: 3.6 ring dilute, 158865.doc • 90- 201217392 optionally substituted c3-6 aryl and optionally substituted c3_6 heteroaryl; rAA4 can be hydrogen; rAA5 optional From hydrogen, -orAA9 and -oc(=o)raa1q; rAA6 may be selected from hydrogen, halogen, -orAA11 and -oc(=o)rAA12; or both rAA5 and rAA6 may be oxygen atoms and The carbonyl groups are linked together; rAA7 may be selected from the group consisting of hydrogen, halogen, optionally substituted Cb6 alkyl, -ORAA13 and -0C(=0)RAA14; RAA8 may be hydrogen or optionally substituted Cw alkyl; RAA9, RAAn And RAA13 may be independently selected from hydrogen and optionally substituted Cm alkyl; and pAAlO, RAA12 and RAA14 may be independently selected from optionally substituted ci6 alkyl and optionally substituted C3-6 cycloalkyl. A non-limiting list of examples of AA) compounds and their phosphates includes the compounds numbered 7000 to 7077 in Figures 8A-8I. In some embodiments, Formula (AA) cannot be Compounds 7044, 7045, 7046 '7047, 7048 , 7049, 7050 '7072 ' 7073 ' 7074 , 7075 ' 7076 or 7077 ° In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I) or pharmaceutically acceptable thereof A pharmaceutical composition of an acceptable salt can be used in combination with a compound of formula (BB) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (BB) or a pharmaceutically acceptable salt thereof (see 2010) US Provisional Application No. 61/426,471, filed on December 22nd, Content is incorporated herein by reference in their entirety in):

158865.doc •91· 201217392 where B can be an optionally substituted heterocyclic test group or an optionally substituted heterocyclic base having a protected amine group; XBB can be oxime (oxygen) or 8 (sulfur) RBBI may be selected from _zbb_rBB9, optionally substituted N-linked amino acid and optionally substituted N-linked amino acid ester derivative; ZBB may be selected from the group consisting of hydrazine (oxygen), S (sulfur) and N (RBB1Q); RBB2 and RBB3 may be independently selected from hydrogen, optionally substituted C!·6 alkyl, optionally substituted c2 6 alkenyl, optionally substituted C2·6 alkynyl, optionally Substituted Ci 6 haloalkyl and optionally substituted aryl (C!.6 alkyl); or RBB2 together with RBB3 form a group selected from the group consisting of C: 3.6 cycloalkyl optionally substituted Optionally substituted CM cycloalkenyl, optionally substituted A.6 aryl and optionally substituted C3-6 heteroaryl; rBB4 may be selected from the group consisting of hydrogen, halogen, azide, cyano, optionally Substituted Cw alkyl, optionally substituted C2 6 alkenyl, optionally substituted C2. 6 alkynyl and optionally substituted allenyl; rbb5 can be hydrogen or optionally taken C丨·6 alkyl; rBB6 may be selected from hydrogen, halogen, azide, amine, cyano, optionally substituted C 1-6 alkyl, 〇 〇 RbB11 & -OC (=0) Rbb12; 11 grab 7 may be selected from the group consisting of hydrogen, halogen, azido, cyano, optionally substituted C!_6 alkyl, -〇RBB13 and _〇C(=〇)RBB丨4; rBB8 may be selected from hydrogen, halogen , azido, cyano, optionally substituted c16 alkyl, -ORBB15 and ·ΟΟροπΒΒΜ; RBB9 may be selected from optionally substituted leukoxyl, optionally substituted dilute groups, optionally substituted fast radicals Substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted Aryl (Ci.6 alkyl), optionally substituted heteroaryl (Ci-6 alkyl) and optionally substituted heterocyclic (Ci 6 alkyl); rBBi 〇 158865.doc -92· 201217392 It may be selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl Optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, optionally substituted aryl (c丨.6 alkyl), optionally substituted heteroaryl (CM alkyl) and optionally substituted heterocyclic group (Cw alkyl); Rbb丨丨, rbb丨3 and rBB丨5 may independently be hydrogen or optionally substituted C..6 alkyl; RBB12, rbbh and rBB10 may independently be optionally substituted C1-6 alkyl or optionally substituted c3 6 cycloalkyl. In some embodiments, at least one of RBB2 and Rbb3 is not hydrogen. A non-limiting list of exemplary formula (BB) compounds includes the compounds numbered 8000-8012 in Figures 9A-9B. A pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I), or a pharmaceutically acceptable salt thereof, in some embodiments, may be combined with a compound of formula (DD) or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising a compound of the formula (DD) or a pharmaceutically acceptable salt thereof, is used in combination (see US Publication No. 2010-0249068, filed on March 19, 2010, which The content is incorporated herein by reference in its entirety:

RDD6 RDD7 Formula (DD) wherein each 222 is independently a double bond or a single bond; ADD1 may be selected from C (carbon), hydrazine (oxygen) and S (sulfur); BDD1 may be optionally substituted heterocyclic ring Base or its derivative 158865.doc -93- 201217392 organism; Dd〇i can be selected from C = CH2, CH2, 0 (oxygen), S (sulfur), CHF and CF2; RDD1 can be hydrogen, as appropriate Alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, dialkylaminoalkylene, alkyl-C(=0)-, aryl-C(=0)-, alkane oxyalkyl-C(=0)-, aryloxyalkyl-c(=〇)-, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, RDD1〇_J! a linked amino acid, a diphosphate thereof, a rDD11 ester or a derivative of triphosphate; rDD2 and rDD3 may each independently be selected from hydrogen, optionally substituted Cw alkyl, optionally substituted c2.6 olefin Substituted as appropriate (: 2.6 alkynyl and optionally substituted C!-6 haloalkyl, the restriction that at least one of rDD2 and rDD3 may not be hydrogen; or rDD2 together with rDD3 form a selected from Groups: C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 aryl and C3_6 RDD4 and RDD9 may be independently selected from the group consisting of hydrogen, halogen, -NH2, _NHRDDal, NRDDalRDDbl, _ORDDal, -SRDDal, -CN, -NC, -N3, -N〇2, -N(RDDel)-NRDDalRDDbl, -N (RDDcl)-ORDDal, -S-SRDDal, _C(=0)RDDal, -C( = 0)0RDDal, -C( = 0)NRDDalRDDbl, -0-(C = 0)RDDal,-0-C(= 0) 0RDDal, -0-C (=0) NRDDalRDDbl, -N(RDDcl)-C(=0)NRDDalRDDbl, -S(=0)RDDal, S(=0)2RDDal,_0-S(=0)2NRDDalRDDbl , -N(RDDc1)-S(=0)2NRDDalRDDbl, optionally substituted C]_6 alkyl, optionally substituted C2.6 alkenyl, optionally substituted C2-6 alkynyl, optionally Substituted aralkyl and-0-linked amino acids; RDD5, RDD6 and RDD7 may be independently absent or selected from hydrogen, _, -NH2, -NHRDDa, NRDDalRDDbl, -ORDDal, -SRDDal, -CN , -NC, -N3, -N〇2, -N(RDDcl)-NRDDalRDDbl, -N(RDDc1) -〇RDDal, -S-SRDDal, -C( = 0)RDDal, -C( = 0)0RDDal, 158865.doc -94· 201217392 -C(=0)NRDDalRDDbl,-0-(C=0)RDDal,-0-C(=0)0RDDal, -Ο- C(=0)NRDDalRDDbl, -N(RDDcl) -C(=0)NRDDalRDDbl, -S(=0)RDDal, S(=0)2RDDal,-0-S(=0)2NRDDalRDDbl, -N(RDD Cl)-S(=0)2NRDDalRDDbl, optionally substituted Cw alkyl, optionally substituted C2.6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted aralkyl and -〇-linked amino acid; or RDD6 together with RDD7 forms -0-C(=0)-0·; RDD8 may be absent or selected from the group consisting of hydrogen, lS, -NH2, -NHRDDal, NRDDalRDDbl, _〇RDDal, _SRDDal, _CN, -Nc, _n3, _n〇2, _N(RDDcl)_ NRDDalRDDbl, -N(RDDcl)-ORDDal, _S-SRDDal, -C(=0)RDDal, -C(= 0) 0RDDal, -C(=0)NRDDalRDDbl, -0-C(=0)0RDDal, -0-C(=0)NRDDalRDDbl, -N(RDDcl)-C(=0)NRDDalRDDbl, -S(=0 RDDal, S(=0)2RDDal, -0-S(=0)2NRDDalRDDbl, -N(RDDcl)-S(=0)2NRDDalRDDbl, optionally substituted Cw alkyl, optionally substituted C2_6 alkenyl , optionally substituted C2-6 alkynyl, optionally substituted haloalkyl, optionally substituted hydroxyalkyl and - hydrazine-linked amino acid, or when indicated by bis to RDD7 When it is a double bond, RDD7 is a C2.6 alkylene group and RDD8 is absent; RDDal, RDDbl and RDDel may each independently be selected from hydrogen, optionally substituted alkyl, Substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl and optionally substituted heteroaryl ( CN6 alkyl); RDD10 may be selected from 0-, -OH, optionally substituted aryloxy or aryl-hydrazine-,

, alkyl-c(=o)-o-ch2-o-, alkyl 158865.doc -95- 201217392 -C(=0)-S-CH2CH2-0- and -N-linked amino acid; RDDn It may be selected from 〇·, -〇H, optionally substituted aryloxy or aryl _ 0 _,

, alkyl-c(=o)-o-ch2-o-, alkyl-C(=0)-S-CH2CH2-0- and a linked amino acid; each rDD12 and each RDD13 can independently be -CsN Or optionally substituted substituents selected from the group consisting of Cw organocarbonyl, Cw alkoxycarbonyl and C.8organidoaminocarbonyl; each RDD14 can be hydrogen or optionally substituted (^-6 alkyl; each claw (10) independently

It is 1 or 2' and if both RDD10 and rDdu are |_〇, each RDD12, each RDD13, each RDD14, and each mDD may be the same or different. And R. Some of the embodiments described herein are directed to methods of ameliorating or treating a viral infection, which may comprise administering a virus-infected cell with a therapeutically effective amount of a compound of formula (1) (including a compound of formula (Ια)) Or a pharmaceutically acceptable salt thereof and one or more agents selected from the group consisting of: interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5 inhibitor, antiviral compound; formula (AA) a compound, a monophosphate thereof, a dibasic acid ester and/or a triphosphate; a compound of the formula (BB) and a compound of the formula (DD), or a pharmaceutically acceptable salt of any of the above compounds. A method for ameliorating or treating a viral infection 158865.doc-96·201217392, which may comprise administering a therapeutically effective amount of a compound of formula (i) (including a compound of formula (Ια)) or a medicament thereof to an individual having a viral infection. Learn to learn a salt and one or more agents selected from the group consisting of interferons, ribavirins, HCV protease inhibitors, HCV polymerase inhibitors, NS5 inhibitors, antiviral compounds; compounds of formula (AA), monophosphates thereof, a bisphosphate and/or triphosphate; a compound of formula (BB), and a compound of formula (DD), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments described herein are directed to methods of inhibiting viral replication. Which may comprise contacting the virus-infected cell with an effective amount of a compound of formula (I) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof, and one or more agents selected from the group consisting of interferon, Ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound; a compound of the formula (ΑΑ), a monophosphate, a diphosphate thereof and/or a triphosphate; a compound of the formula (ΒΒ), and A compound of formula (DD), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments described herein are directed to methods of ameliorating or treating a viral infection, which may comprise infecting an infected virus. The cells are contacted with a therapeutically effective amount of a compound of formula (I) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof, and one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, An HCV polymerase inhibitor, an NS5 inhibitor, an antiviral compound, a compound of formula (AA), a compound of formula (BB), and a compound of formula (DD), or a pharmaceutically acceptable salt of any of the foregoing. Some embodiments are directed to methods of ameliorating or treating a viral infection, which can comprise administering to a subject having a viral infection a therapeutically effective amount of a compound of formula (I) 158S65.doc • 97-201217392 (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof and one or more agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (AA), (BB) a compound, and a compound of formula (DD), or a pharmaceutically acceptable salt of any of the above. Some embodiments described herein are directed to methods of inhibiting viral replication, which may comprise sensitizing a virus-infecting cell with an effective amount of a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof, and or A plurality of agents selected from the group consisting of interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound, compound of formula (AA), compound of formula (bb), and formula (dd) A compound, or a pharmaceutically acceptable salt of any of the above compounds. In some embodiments, a compound of formula (1), including a compound of formula (Ια), or a pharmaceutically acceptable salt thereof, can be administered in a single pharmaceutical composition with one or more other pharmaceutical agents. In some embodiments, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can be administered in combination with one or more other pharmaceutical agents in two or more separate pharmaceutical compositions. For example, a compound of formula (I) (including a compound of formula (Ια)) or a pharmaceutically acceptable lozenge composition thereof, and at least one other agent can be administered as a second pharmaceutical composition . If at least two other agents are present, then one or more of the other agents may be in a first pharmaceutical mouth comprising a compound of formula (1), including a compound of formula (Ια), or a pharmaceutically acceptable salt thereof, and At least one additional additional agent can be in the second pharmaceutical composition. 158865.doc -98-201217392 When using a compound of formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more other pharmaceutical agents The amount administered and the time course of administration are within the knowledge of those skilled in the art. For example, when a standard of care for a known standard of care is administered using the amount of administration and time course of administration of the art, in addition to the therapies, an effective amount and dosage regimen as described herein can also be used. (1) a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula () or a pharmaceutically acceptable salt thereof, or may be administered using an effective amount and a dosing schedule as described herein One of the agents for substance replacement combination therapy. The administration of the compound of formula (1) or a pharmaceutically acceptable salt thereof may be different from the order in which one or more other pharmaceutical agents are administered. In some embodiments, a compound of formula (1) (including a compound of formula (Ια)) or a pharmaceutically acceptable salt thereof can be administered prior to all other agents. In other embodiments, the compound of formula (1) (including a compound of formula (10)) or a pharmaceutically acceptable salt thereof can be administered prior to at least one other agent. In other embodiments, the compound of formula (1) (including the compound of formula (10)) or a pharmaceutically acceptable salt thereof can be administered simultaneously with one or more other pharmaceutical agents. In other embodiments, the compound of formula (1) (including the compound of formula (10)) or a pharmaceutically acceptable salt thereof can be administered after administration of at least one other agent. In some embodiments, the compound of formula (1) (including the compound of formula (10)) or a pharmaceutically acceptable salt thereof can be administered after administration of all other agents. In an embodiment, the combination of the compound of formula (1) or its pharmaceutically acceptable sleep with one or more of the other agents of Figures 2-6 and _, including its physician; the salt and prodrug received, may produce an additive effect. . In some embodiments, l5SS65.doc •99-201217392, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more other agents of Figures 2-6 and 8-10 (including pharmaceutically acceptable Combination of salts and prodrugs can produce a synergistic effect. In some embodiments, a compound of formula (1) or a pharmaceutically acceptable salt thereof, and one or more other agents of Figures 2-6 and 8-10 (including The combination of pharmaceutically acceptable salts and prodrugs produces a strong synergistic effect. In some embodiments, a combination of a compound of formula (1) or a pharmaceutically acceptable salt thereof with one or more other pharmaceutical agents of Figures 2-6 and 8-10, including pharmaceutically acceptable salts and prodrugs thereof No antagonistic effect. The term "drying effect" as used herein means that the activity of the combination of the compounds is lower than the sum of the activities of the respective compounds in the combination when the activity of each compound is determined individually (i.e., in the form of a single compound). The term "synergistic effect" as used herein means that the combination of the compounds of the stomach compound is greater than the sum of the activities of the individual compounds in the combination when the activity of each compound is determined individually. As used herein, the term "additive effect" means that the activity of the combination of compounds is about equal to the sum of the individual compounds in the combination when the activity of each compound is determined individually. A potential advantage of using a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more of the other pharmaceutical agents of Figures 2-6 and 8_1, including pharmaceutically acceptable salts and prodrugs thereof, Figures 2-6 and 8_1, one or more compounds (including pharmaceutically acceptable salts and prodrugs thereof) are effective in treating the disease conditions (e.g., HCV) disclosed herein as compared to when administered in Figures 2-6 and 8 -10 The amount required to achieve the same therapeutic result when one or more compounds (including pharmaceutically acceptable salts and prodrugs thereof) are administered without the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof reduce. For example, the amounts of the compounds (including their pharmaceutically acceptable salts and prodrugs) in Figures 2-6 and 8_1〇158865.doc •100·201217392 may be less than the compounds in Figures 2-6 and 8-10 ( Including the pharmaceutically acceptable salts and expectorants thereof, the amount required to achieve the same viral load reduction effect when administered in a monotherapy form. Another combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with one or more of the other pharmaceutical agents of Figures 2.6 and 8-10, including pharmaceutically acceptable salts and prodrugs thereof A potential advantage is that the use of two or more compounds having different mechanisms of action can cause a greater impediment to the production of a resistant strain compared to when the compound is administered in a monotherapy form. Other advantages of using a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more other pharmaceutical agents (including pharmaceutically acceptable salts and prodrugs thereof) of Figures 2-6 and 8 may include (1) a compound or a pharmaceutically acceptable salt thereof having little or no cross-resistance with one or more of the other agents of Figures 2-6 and 8_1 (including pharmaceutically acceptable salts and prodrugs thereof); (1) a compound or a pharmaceutically acceptable salt thereof is different from the elimination route of - or a plurality of other pharmaceutical agents (including pharmaceutically acceptable salts and prodrugs thereof) in Figures 2-6 and 8; a compound of the formula (1) or The pharmaceutically acceptable salt has little to no overlap toxicity with one or more of the other agents of Figures 2-6 and 8-10, including its pharmaceutically acceptable salts and prodrugs; there is almost no cytochrome Ρ450 To have no significant effect; and/or the compound of formula (1) or its pharmaceutically acceptable salt and other agents of Figures 2-6 and 8-10, and one of the other agents (including its medical pleasure) There is almost no pharmacokinetic interaction between acceptable salts and prodrugs. (1) A non-limiting list of exemplified combinations of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the above-mentioned I58865.doc 201217392, with one or more other agents, is provided in Tables A, B, 匚And D. Each of the compounds numbered X and Y in Tables A, B, c and D has the corresponding names and/or structures provided in Figures 2 to 1〇. The compounds numbered in Tables A, B, C and D include pharmaceutically acceptable salts of such compounds and pharmaceutical compositions containing such compounds or pharmaceutically acceptable salts thereof. For example, 1〇〇1 includes a compound corresponding to 1001, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising Compound 1001 and/or a pharmaceutically acceptable salt thereof. The combinations exemplified in Tables A, B, C and D are designated by the formula: γ, which represents the combination of Compound X and the compound oxime. For example, a combination designated as 1001:6001 in the table indicates a combination of Compound 1 〇〇1 and Compound 〇〇1, including a pharmaceutically acceptable salt of Compound 1001 and/or 6001, and includes Compound 1001 and A pharmaceutical composition of 6001 (including a pharmaceutical composition comprising a compound 〇〇1 and/or a pharmaceutically acceptable salt of the compound 6001). Thus, the combination designated as 1001:6001 in Table a indicates Tetravir (Compound 1001, as shown in Figure 2) and

0一Ρ—〇-1

, a combination of hydrazine (compound 6001, as shown in FIG. 7A) includes a pharmaceutically acceptable salt of the compound 1001 and/or 6.1, and a pharmaceutical composition comprising the compounds 1001 and 6001 (including the compound 1001 and / or a pharmaceutical composition of a pharmaceutically acceptable salt of compound 6001). Each combination provided in Tables A, B, C and D can be used with one, two, three or more of the other agents described herein. In some embodiments, the embodiments described herein, combinations of agents can be used to treat, ameliorate, and/or inhibit viral and/or viral infections, wherein the virus can be HCV and the virus can be infected. Infected with HCV virus. Table A: Exemplary Combinations of Compound X and Compound Y

X: Y

X: Y

X: Y

X: Y

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X:Y 1001 : 6042 1002 : 6042 1003 : 6042 1004 : 6042 1005 : 6042 1006 : 6042 1007 : 6042 1008 : 6042 1009 : 6042 1010 : 6042 1011 : 6042 1012 : 6042 1013 : 6042 1014 : 6042 2001 : 6042 2002 : 6042 2003 : 6042 2004 : 6042 2005 : 6042 2006 : 6042 2007 : 6042 2008 : 6042 2009 : 6042 2010 : 6042 3001 : 6042 3002 : 6042 3003 : 6042 3004 : 6042 3005 : 6042 3006 : 6042 3007 : 6042 3008 : 6042 4001 : 6042 4002 : 6042 4003 : 6042 4004 : 6042 4005 : 6042 5001 : 6042 5002 : 6042 1001 : 6043 1002 : 6043 1003 : 6043 1004 : 6043 1005 : 6043 1006 : 6043 1007 : 6043 1008 : 6043 1009 : 6043 1010 : 6043 1011 : 6043 1012 : 6043 1013 : 6043 1014 : 6043 2001 : 6043 2002 : 6043 2003 : 6043 2004 : 6043 2005 : 6043 2006 : 6043 2007 : 6043 2008 : 6043 2009 : 6043 2010 : 6043 3001 : 6043 3002 : 6043 3003 : 6043 3004 : 6043 3005 : 6043 3006 : 6043 3007 : 6043 3008 : 6043 4001 : 6043 4002 : 6043 4003 : 6043 4004 : 6043 4005 : 6043 5001 : 6043 5002 : 6043 1001 : 6044 1002 : 6044 1003 : 6044 1004 : 6044 1005 : 6044 100 6 : 6044 1007 : 6044 1008 : 6044 1009 : 6044 1010 : 6044 1011 : 6044 1012 : 6044 1013 : 6044 1014 : 6044 2001 : 6044 2002 : 6044 2003 : 6044 2004 : 6044 2005 : 6044 2006 : 6044 2007 : 6044 2008 : 6044 2009 : 6044 2010 : 6044 3001 : 6044 3002 : 6044 3003 : 6044 3004 : 6044 3005 : 6044 3006 : 6044 3007 : 6044 3008 : 6044 4001 : 6044 4002 : 6044 4003 : 6044 4004 : 6044 4005 : 6044 5001 : 6044 5002 : 6044 1001 : 6045 1002 : 6045 1003 : 6045 1004 : 6045 1005 : 6045 1006 : 6045 1007 : 6045 1008 : 6045 1009 : 6045 1010 : 6045 1011 : 6045 1012 : 6045 1013 : 6045 1014 : 6045 2001 : 6045 2002 : 6045 2003 : 6045 2004 : 6045 2005 : 6045 2006 : 6045 2007 : 6045 2008 : 6045 2009 : 6045 2010 : 6045 3001 : 6045 3002 : 6045 3003 : 6045 3004 : 6045 3005 : 6045 3006 : 6045 3007 : 6045 3008 : 6045 4001 : 6045 4002 : 6045 4003 : 6045 4004 : 6045 4005 : 6045 5001 : 6045 5002 : 6045 1001 : 6046 1002 : 6046 1003 : 6046 1004 : 6046 1005 : 6046 1006 : 6046 1007 : 6046 1008 : 6046 1009 : 6046 1010:6046 1011 :6046 1012 : 6046 1013 : 6046 1014:6046 2001 : 6046 2002 : 6046 2003 : 6046 2004 : 6046 2005 : 6046 2006 : 6046 2007 : 6046 2008 : 6046 2009 : 6046 2010 : 6046 3001 : 6046 3002 : 6046 3003 : 6046 3004 : 6046 3005 : 6046 3006 : 6046 3007 : 6046 3008 : 6046 4001 : 6046 4002 : 6046 4003 : 6046 4004 : 6046 4005 : 6046 5001 : 6046 5002 : 6046 1001 : 6047 1002 : 6047 1003 : 6047 1004 : 6047 1005 : 6047 1006 : 6047 1007 : 6047 1008 : 6047 1009 : 6047 1010 : 6047 1011 : 6047 1012 : 6047 1013 : 6047 1014 : 6047 2001 : 6047 2002 : 6047 2003 : 6047 2004 : 6047 2005 : 6047 2006 : 6047 2007 : 6047 2008 : 6047 2009 : 6047 2010 : 6047 3001 : 6047 3002 : 6047 3003 : 6047 3004 : 6047 3005 : 6047 3006 : 6047 3007 : 6047 3008 : 6047 4001 : 6047 4002 : 6047 4003 : 6047 4004 : 6047 4005 : 6047 5001 : 6047 5002 : 6047 1001 : 6048 1002 : 6048 1003 : 6048 1004 : 6048 1005 : 6048 1006 : 6048 1007 : 6048 1008 : 6048 1009 : 6048 1010 : 6048 1011 : 6048 1012 : 6048 1013 : 6048 1014 : 6048 2001 : 6048 2002 : 6048 2003 : 6048 2004 : 6048 2005 : 6048 2006 : 6048 2007 : 6048 2008 : 6048 2009 : 6048 2010 : 6048 3001 : 6048 3002 : 6048 3003 : 6048 3004 : 6048 3005 : 6048 3006 : 6048 3007 : 6048 3008 : 6048 4001 : 6048 4002 : 6048 4003 : 6048 4004 : 6048 4005 : 6048 5001 : 6048 5002 : 6048 158865.doc 109- 201217392 X: Υ

X:Y

X: Y

X: Y

X:Y

X:Y

X:Y 1001 : 6049 1002 : 6049 1003 : 6049 1004 : 6049 1005 : 6049 1006 : 6049 1007 : 6049 1008 : 6049 1009 : 6049 1010 : 6049 1011 : 6049 1012 : 6049 1013 : 6049 1014 : 6049 2001 : 6049 2002 : 6049 2003 : 6049 2004 : 6049 2005 : 6049 2006 : 6049 2007 : 6049 2008 : 6049 2009 : 6049 2010 : 6049 3001 : 6049 3002 : 6049 3003 : 6049 3004 : 6049 3005 : 6049 3006 : 6049 3007 : 6049 3008 : 6049 4001 : 6049 4002 : 6049 4003 : 6049 4004 : 6049 4005 : 6049 5001 : 6049 5002 : 6049 1001 : 6050 1002 : 6050 1003 : 6050 1004 : 6050 1005 : 6050 1006 : 6050 1007 : 6050 1008 : 6050 1009 : 6050 1010 : 6050 1011 : 6050 1012 : 6050 1013 : 6050 1014 : 6050 2001 : 6050 2002 : 6050 2003 : 6050 2004 : 6050 2005 : 6050 2006 : 6050 2007 : 6050 2008 : 6050 2009 : 6050 2010 : 6050 3001 : 6050 3002 : 6050 3003 : 6050 3004 : 6050 3005 : 6050 3006 : 6050 3007 : 6050 3008 : 6050 4001 : 6050 4002 : 6050 4003 : 6050 4004 : 6050 4005 : 6050 5001 : 6050 5002 : 6050 1001 : 6051 1002 : 6051 1003 : 6051 1004 : 6051 1005 : 6051 100 6 : 6051 1007 : 6051 1008 : 6051 1009 : 6051 1010: 6051 1011 : 6051 1012: 6051 1013 : 6051 1014: 6051 2001 : 6051 2002 : 6051 2003 : 6051 2004 : 6051 2005 : 6051 2006 : 6051 2007 : 6051 2008 : 6051 2009 : 6051 2010 : 6051 3001 : 6051 3002 : 6051 3003 : 6051 3004 : 6051 3005 : 6051 3006 : 6051 3007 : 6051 3008 : 6051 4001 : 6051 4002 : 6051 4003 : 6051 4004 : 6051 4005 : 6051 5001 : 6051 5002 : 6051 1001 : 6052 1002 : 6052 1003 : 6052 1004 : 6052 1005 : 6052 1006 : 6052 1007 : 6052 1008 : 6052 1009 : 6052 1010 : 6052 1011 : 6052 1012 : 6052 1013 : 6052 1014 : 6052 2001 : 6052 2002 : 6052 2003 : 6052 2004 : 6052 2005 : 6052 2006 : 6052 2007 : 6052 2008 : 6052 2009 : 6052 2010 : 6052 3001 : 6052 3002 : 6052 3003 : 6052 3004 : 6052 3005 : 6052 3006 : 6052 3007 : 6052 3008 : 6052 4001 : 6052 4002 : 6052 4003 : 6052 4004 : 6052 4005 : 6052 5001 : 6052 5002 : 6052 1001 : 6053 1002 : 6053 1003 : 6053 1004 : 6053 1005 : 6053 1006 : 6053 1007 : 6053 1008 : 6053 1009 : 6053 1010:6053 1011 :6053 1012 : 605 3 1013 : 6053 1014 : 6053 2001 : 6053 2002 : 6053 2003 : 6053 2004 : 6053 2005 : 6053 2006 : 6053 2007 : 6053 2008 : 6053 2009 : 6053 2010 : 6053 3001 : 6053 3002 : 6053 3003 : 6053 3004 : 6053 3005 : 6053 3006 : 6053 3007 : 6053 3008 : 6053 4001 : 6053 4002 : 6053 4003 : 6053 4004 : 6053 4005 : 6053 5001 : 6053 5002 : 6053 1001 : 6054 1002 : 6054 1003 : 6054 1004 : 6054 1005 : 6054 1006 : 6054 1007 : 6054 1008 : 6054 1009 : 6054 1010: 6054 1011 : 6054 1012: 6054 1013 : 6054 1014 : 6054 2001 : 6054 2002 : 6054 2003 : 6054 2004 : 6054 2005 : 6054 2006 : 6054 2007 : 6054 2008 : 6054 2009 : 6054 2010 : 6054 3001 : 6054 3002 : 6054 3003 : 6054 3004 : 6054 3005 : 6054 3006 : 6054 3007 : 6054 3008 : 6054 4001 : 6054 4002 : 6054 4003 : 6054 4004 : 6054 4005 : 6054 5001 : 6054 5002 : 6054 1001 : 6055 1002 : 6055 1003 : 6055 1004 : 6055 1005 : 6055 1006 : 6055 1007 : 6055 1008 : 6055 1009 : 6055 1010 : 6055 1011 : 6055 1012 : 6055 1013 : 6055 1014 : 6055 2001 : 6055 2002 : 6055 2003 : 6055 2004 : 60 55 2005 : 6055 2006 : 6055 2007 : 6055 2008 : 6055 2009 : 6055 2010 : 6055 3001 : 6055 3002 : 6055 3003 : 6055 3004 : 6055 3005 : 6055 3006 : 6055 3007 : 6055 3008 : 6055 4001 : 6055 4002 : 6055 4003 : 6055 4004 : 6055 4005 : 6055 5001 : 6055 5002 : 6055 158865.doc -110- 201217392

X: Y 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 3001 3002 3003 3004 3005 3006 3007 3008 4001 4002 4003 4004 4005 5001 5002 : 6057 : 6057 : 6057 : 6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 :6057 Χ:Υ 1001 : 6056 1002 : 6056 1003 : 6056 1004 : 6056 1005 : 6056 1006 : 6056 1007 : 6056 1008 : 6056 1009 : 6056 1010:6056 1011 :6056 1012:6056 1013 :6056 1014:6056 2001 : 6056 2002 : 6056 2003 : 6056 2004 : 6056 2005 : 6056 2006 : 6056 2007 : 6056 2008 : 6056 2009 : 6056 2010 : 6056 3001 : 6056 3002 : 6056 3003 : 6056 3004 : 6056 3005 : 6056 3006 : 6056 3007 : 6056 3008 : 6056 4001 : 6056 4002 : 6056 4003 : 6056 4004 : 6056 4005 : 6056 5001 : 6056 5002 : 6056

X: Y 1001 : 6058 1002 : 6058 1003 : 6058 1004:6058 1005 : 6058 1006 : 6058 1007 : 6058 1008: 6058 1009 : 6058 1010 : 6058 1011: 6058 1012:6058 1013 : 6058 1014:6058 2001 : 6058 2002 : 6058 2003 : 6058 2004 : 6058 2005 : 6058 2006 : 6058 2007 : 6058 2008: 6058 2009 : 6058 2010: 6058 3001 : 6058 3002 : 6058 3003 : 6058 3004 : 6058 3005 : 6058 3006 : 6058 3007 : 6058 3008 : 6058 4001 : 6058 4002 : 6058 4003 : 6058 4004: 6058 4005 : 6058 5001 : 6058 5002: 6058

X: Y 1001 : 6059 1002 : 6059 1003 : 6059 1004 : 6059 1005 : 6059 1006 : 6059 1007 : 6059 1008 : 6059 1009 : 6059 1010 : 6059 1011 : 6059 1012 : 6059 1013 : 6059 1014 : 6059 2001 : 6059 2002 : 6059 2003 : 6059 2004 : 6059 2005 : 6059 2006 : 6059 2007 : 6059 2008 : 6059 2009 : 6059 2010 : 6059 3001 : 6059 3002 : 6059 3003 : 6059 3004 : 6059 3005 : 6059 3006 : 6059 3007 : 6059 3008 : 6059 4001 : 6059 4002 : 6059 4003 : 6059 4004 : 6059 4005 : 6059 5001 : 6059 5002 : 6059

X: Y 1001 : 6060 1002 : 6060 1003 : 6060 1004 : 6060 1005 : 6060 1006 : 6060 1007 : 6060 1008 : 6060 1009 : 6060 1010 : 6060 1011 : 6060 1012 : 6060 1013 : 6060 1014 : 6060 2001 : 6060 2002 : 6060 2003 : 6060 2004 : 6060 2005 : 6060 2006 : 6060 2007 : 6060 2008 : 6060 2009 : 6060 2010 : 6060 3001 : 6060 3002 : 6060 3003 : 6060 3004 : 6060 3005 : 6060 3006 : 6060 3007 : 6060 3008 : 6060 4001 : 6060 4002 : 6060 4003 : 6060 4004 : 6060 4005 : 6060 5001: 6060 5002 : 6060

X: Y 1001 : 6061 1002 : 6061 1003 : 6061 1004 : 6061 1005 : 6061 1006 : 6061 1007 : 6061 1008 : 6061 1009 : 6061 1010 : 6061 1011 : 6061 1012 : 6061 1013 : 6061 1014 : 6061 2001 : 6061 2002 : 6061 2003 : 6061 2004 : 6061 2005 : 6061 2006 : 6061 2007 : 6061 2008 : 6061 2009 : 6061 2010 : 6061 3001 : 6061 3002 : 6061 3003 : 6061 3004 : 6061 3005 : 6061 3006 : 6061 3007 : 6061 3008 : 6061 4001 : 6061 4002 : 6061 4003 : 6061 4004 : 6061 4005 : 6061 5001 : 6061 5002 : 6061

X: Y 1001 : 6062 1002 : 6062 1003 : 6062 1004 : 6062 1005 : 6062 1006 : 6062 1007 : 6062 1008 : 6062 1009 : 6062 1010 : 6062 1011 : 6062 1012 : 6062 1013 : 6062 1014 : 6062 2001 : 6062 2002 : 6062 2003 :.6062 2004 : 6062 2005 : 6062 2006 : 6062 2007 : 6062 2008 : 6062 2009 : 6062 2010 : 6062 3001 : 6062 3002 : 6062 3003 : 6062 3004 : 6062 3005 : 6062 3006 : 6062 3007 : 6062 3008 : 6062 4001 : 6062 4002 : 6062 4003 : 6062 4004 : 6062 4005 : 6062 5001 : 6062 5002 : 6062 158865.doc 111- 201217392 X: Υ

X: Y

X: Y

X: Y

X: Y

X:Y

X: Y 1001 : 6063 1002 : 6063 1003 : 6063 1004 : 6063 1005 : 6063 1006 : 6063 1007 : 6063 1008 : 6063 1009 : 6063 1010 : 6063 1011 : 6063 1012 : 6063 1013 : 6063 1014 : 6063 2001 : 6063 2002 : 6063 2003 : 6063 2004 : 6063 2005 : 6063 2006 : 6063 2007 : 6063 2008 : 6063 2009 : 6063 2010 : 6063 3001 : 6063 3002 : 6063 3003 : 6063 3004 : 6063 3005 : 6063 3006 : 6063 3007 : 6063 3008 : 6063 4001 : 6063 4002 : 6063 4003 : 6063 4004 : 6063 4005 : 6063 5001 : 6063 5002 : 6063 1001 : 6064 1002 : 6064 1003 : 6064 1004 : 6064 1005 : 6064 1006 : 6064 1007 : 6064 1008 : 6064 1009 : 6064 1010 : 6064 1011 : 6064 1012 : 6064 1013 : 6064 1014 : 6064 2001 : 6064 2002 : 6064 2003 : 6064 2004 : 6064 2005 : 6064 2006 : 6064 2007 : 6064 2008 : 6064 2009 : 6064 2010 : 6064 3001 : 6064 3002 : 6064 3003 : 6064 3004 : 6064 3005 : 6064 3006 : 6064 3007 : 6064 3008 : 6064 4001 : 6064 4002 : 6064 4003 : 6064 4004 : 6064 4005 : 6064 5001 : 6064 5002 : 6064 1001 : 6065 1002 : 6065 1003 : 6065 1004 : 6065 1005 : 6065 1 006 : 6065 1007 : 6065 1008 : 6065 1009 : 6065 1010 : 6065 1011 : 6065 1012 : 6065 1013 : 6065 1014 : 6065 2001 : 6065 2002 : 6065 2003 : 6065 2004 : 6065 2005 : 6065 2006 : 6065 2007 : 6065 2008 : 6065 2009 : 6065 2010 : 6065 3001 : 6065 3002 : 6065 3003 : 6065 3004 : 6065 3005 : 6065 3006 : 6065 3007 : 6065 3008 : 6065 4001 : 6065 4002 : 6065 4003 : 6065 4004 : 6065 4005 : 6065 5001 : 6065 5002 : 6065 1001 : 6066 1002 : 6066 1003 : 6066 1004 : 6066 1005 : 6066 1006 : 6066 1007 : 6066 1008 : 6066 1009 : 6066 1010 : 6066 1011 : 6066 1012 : 6066 1013 : 6066 1014 : 6066 2001 : 6066 2002 : 6066 2003 : 6066 2004 : 6066 2005 : 6066 2006 : 6066 2007 : 6066 2008 : 6066 2009 : 6066 2010 : 6066 3001 : 6066 3002 : 6066 3003 : 6066 3004 : 6066 3005 : 6066 3006 : 6066 3007 : 6066 3008 : 6066 4001 : 6066 4002 : 6066 4003 : 6066 4004 : 6066 4005 : 6066 5001 : 6066 5002 : 6066 1001 : 6067 1002 : 6067 1003 : 6067 1004 : 6067 1005 : 6067 1006 : 6067 1007 : 6067 1008 : 6067 1009 : 6067 1010 : 6067 1011 :60 67 1012 : 6067 1013 : 6067 1014 : 6067 2001 : 6067 2002 : 6067 2003 : 6067 2004 : 6067 2005 : 6067 2006 : 6067 2007 : 6067 2008 : 6067 2009 : 6067 2010 : 6067 3001 : 6067 3002 : 6067 3003 : 6067 3004 : 6067 3005 : 6067 3006 : 6067 3007 : 6067 3008 : 6067 4001 : 6067 4002 : 6067 4003 : 6067 4004 : 6067 4005 : 6067 5001 : 6067 5002 : 6067 1001 : 6068 1002 : 6068 1003 : 6068 1004 : 6068 1005 : 6068 1006 : 6068 1007 : 6068 1008 : 6068 1009 : 6068 1010 : 6068 1011 : 6068 1012 : 6068 1013 : 6068 1014 : 6068 2001 : 6068 2002 : 6068 2003 : 6068 2004 : 6068 2005 : 6068 2006 : 6068 2007 : 6068 2008 : 6068 2009 : 6068 2010 : 6068 3001 : 6068 3002 : 6068 3003 : 6068 3004 : 6068 3005 : 6068 3006 : 6068 3007 : 6068 3008 : 6068 4001 : 6068 4002 : 6068 4003 : 6068 4004 : 6068 4005 : 6068 5001 : 6068 5002 : 6068 1001 : 6069 1002 : 6069 1003 : 6069 1004 : 6069 1005 : 6069 1006 : 6069 1007 : 6069 1008 : 6069 1009 : 6069 1010 : 6069 1011 : 6069 1012 : 6069 1013 : 6069 1014 : 6069 2001 : 6069 2002 : 6069 20 03 : 6069 2004 : 6069 2005 : 6069 2006 : 6069 2007 : 6069 2008 : 6069 2009 : 6069 2010 : 6069 3001 : 6069 3002 : 6069 3003 : 6069 3004 : 6069 3005 : 6069 3006 : 6069 3007 : 6069 3008 : 6069 4001 : 6069 4002 : 6069 4003 : 6069 4004 : 6069 4005 : 6069 5001 : 6069 5002 : 6069 158865.doc 112 201217392 X: Υ

X:Y

X: Y

X:Y Χ:Υ X: Υ X: Υ 1001 : 6070 1002 : 6070 1003 : 6070 1004 : 6070 1005 : 6070 1006 : 6070 1007 : 6070 1008 : 6070 1009 : 6070 1010 : 6070 1011 : 6070 1012 : 6070 1013 : 6070 1014:6070 2001 : 6070 2002 : 6070 2003 : 6070 2004 : 6070 2005 : 6070 2006 : 6070 2007 : 6070 2008 : 6070 2009 : 6070 2010 : 6070 3001 : 6070 3002 : 6070 3003 : 6070 3004 : 6070 3005 : 6070 3006 : 6070 3007 : 6070 3008 : 6070 4001 : 6070 4002 : 6070 4003 : 6070 4004 : 6070 4005 : 6070 5001 : 6070 5002 : 6070 1001 : 6071 1002: 6071 1003 : 6071 1004 : 6071 1005 : 6071 1006 : 6071 1007 : 6071 1008 : 6071 1009 : 6071 1010: 6071 1011 : 6071 1012 : 6071 1013 : 6071 1014 : 6071 2001 : 6071 2002 : 6071 2003 : 6071 2004 : 6071 2005 : 6071 2006 : 6071 2007 : 6071 2008 : 6071 2009 : 6071 2010 : 6071 3001 : 6071 3002 : 6071 3003 : 6071 3004 : 6071 3005 : 6071 3006 : 6071 3007 : 6071 3008 : 6071 4001 : 6071 4002 : 6071 4003 : 6071 4004 : 6071 4005 : 6071 5001 : 6071 5002 : 6071 1001 : 6072 1002 : 6072 1003 : 6072 1004 : 6072 10 05 : 6072 1006 : 6072 1007 : 6072 1008 : 6072 1009 : 6072 1010 : 6072 1011 : 6072 1012 : 6072 1013 : 6072 1014 : 6072 2001 : 6072 2002 : 6072 2003 : 6072 2004 : 6072 2005 : 6072 2006 : 6072 2007 ; 6072 2008 : 6072 2009 : 6072 2010 : 6072 3001 : 6072 3002 : 6072 3003 : 6072 3004 : 6072 3005 : 6072 3006 : 6072 3007 : 6072 3008 : 6072 4001 : 6072 4002 : 6072 4003 : 6072 4004 : 6072 4005 : 6072 5001 : 6072 5002 : 6072 1001 : 6073 1002 : 6073 1003 : 6073 1004 : 6073 1005 : 6073 1006 : 6073 1007 : 6073 1008 : 6073 1009 : 6073 1010 : 6073 1011 : 6073 1012 : 6073 1013 : 6073 1014 : 6073 2001 : 6073 2002 : 6073 2003 : 6073 2004 : 6073 2005 : 6073 2006 : 6073 2007 : 6073 2008 : 6073 2009 : 6073 2010 : 6073 3001 : 6073 3002 : 6073 3003 : 6073 3004 : 6073 3005 : 6073 3006 : 6073 3007 : 6073 3008 : 6073 4001 : 6073 4002 : 6073 4003 : 6073 4004 : 6073 4005 : 6073 5001 : 6073 5002 : 6073 1001 : 6074 1002 : 6074 1003 : 6074 1004 : 6074 1005 : 6074 1006 : 6074 1007 : 6074 1008 : 6074 1009 : 6074 1010 : 6074 1011 : 6074 1012 : 6074 1013 : 6074 1014 : 6074 2001 : 6074 2002 : 6074 2003 : 6074 2004 : 6074 2005 : 6074 2006 : 6074 2007 : 6074 2008 : 6074 2009 : 6074 2010 : 6074 3001 : 6074 3002 : 6074 3003 : 6074 3004 : 6074 3005 : 6074 3006 : 6074 3007 : 6074 3008 : 6074 4001 : 6074 4002 : 6074 4003 : 6074 4004 : 6074 4005 : 6074 5001 : 6074 5002 : 6074 1001 : 6075 1002 : 6075 1003 : 6075 1004 : 6075 1005 : 6075 1006 : 6075 1007 : 6075 1008 : 6075 1009 : 6075 1010 : 6075 1011 : 6075 1012 : 6075 1013 : 6075 1014 : 6075 2001 : 6075 2002 : 6075 2003 : 6075 2004 : 6075 2005 : 6075 2006 : 6075 2007 : 6075 2008 : 6075 2009 : 6075 2010 : 6075 3001 : 6075 3002 : 6075 3003 : 6075 3004 : 6075 3005 : 6075 3006 : 6075 3007 : 6075 3008 : 6075 4001 : 6075 4002 : 6075 4003 : 6075 4004 : 6075 4005 : 6075 5001 : 6075 5002 : 6075 1001 : 6076 1002 : 6076 1003 : 6076 1004 : 6076 1005 : 6076 1006 : 6076 1007 : 6076 1008 : 6076 1009 : 6076 1010 : 6076 1011 : 6076 1012 : 6076 1013 : 6076 1014 : 6076 2001 : 60762002 : 6076 2003 : 6076 2004 : 6076 2005 : 6076 2006 : 6076 2007 : 6076 2008 : 6076 2009 : 6076 2010 : 6076 3001 : 6076 3002 : 6076 3003 : 6076 3004 : 6076 3005 : 6076 3006 : 6076 3007 : 6076 3008 : 6076 4001 : 6076 4002 : 6076 4003 : 6076 4004 : 6076 4005 : 6076 5001 : 6076 5002 : 6076 158865.doc 113- 201217392 X: Υ X: YX:YX: Υ X: Υ X: Υ X: Υ 1001 : 6077 1014 : 6077 3003 : 6077 1001 : 6078 1014 : 6078 3003 : 6078 1002 : 6077 2001 : 6077 3004 : 6077 1002 : 6078 2001 : 6078 3004 : 6078 1003 : 6077 2002 : 6077 3005 : 6077 1003 : 6078 2002 : 6078 3005 : 6078 1004 : 6077 2003 : 6077 3006 : 6077 1004 : 6078 2003 : 6078 3006 : 6078 1005 : 6077 2004 : 6077 3007 : 6077 1005 : 6078 2004 : 6078 3007 : 6078 1006 : 6077 2005 : 6077 3008 : 6077 1006 : 6078 2005 : 6078 3008 : 6078 1007 : 6077 2006 : 6077 4001 : 6077 1007 : 6078 2006 : 6078 4001 : 6078 — 1008 : 6077 2007 : 6077 4002 : 6077 1008 : 6078 2007 : 6078 4002 : 6078 1009 : 6077 2008 : 6077 4003 : 6077 1009 : 6078 200 8 : 6078 4003 : 6078 1010 : 6077 2009 : 6077 4004 : 6077 1010 : 6078 2009 : 6078 4004 : 6078 1011 : 6077 2010 : 6077 4005 : 6077 1011 : 6078 2010 : 6078 4005 : 6078 1012 : 6077 3001 : 6077 5001 : 6077 1012 : 6078 3001 : 6078 5001 : 6078 1013 : 6077 3002 : 6077 5002 : 6077 1013 : 6078 3002 : 6078 5002 : 6078 158865.doc -114- 201217392 Table B: Exemplary combinations of compound X and compound Y Χ: Υ

X:Y

X:Y

X:Y

X:Y

X : Y

X:Y 6000 : 7000 6001 : 7000 6002 : 7000 6003 : 7000 6004 : 7000 6005 : 7000 6006 : 7000 6007 : 7000 6008 : 7000 6009 : 7000 6010 : 7000 6011 : 7000 6012:7000 6013 : 7000 6014 : 7000 6015 : 7000 6016:7000 6017 : 7000 6018 : 7000 6019 : 7000 6020 : 7000 6000 : 7001 6001 : 7001 6002 : 7001 6003 : 7001 6004 : 7001 6005 : 7001 6006 : 7001 6007 : 7001 6008 : 7001 6009 : 7001 6010 : 7001 6011 : 7001 6012 : 7001 6013 : 7001 6014:7001 6015 : 7001 6016:7001 6017 : 7001 6018 : 7001 6019:7001 6020 : 7001 6000 : 7002 6001 : 7002 6002 : 7002 6003 : 7002 6004 : 7002 6005 : 7002 6006 : 7002 6007 : 7002 6008 : 7002 6009 : 7002 6010 : 7002 6011 : 7002 6012 : 7002 6013 : 7002 6014 : 7002 6015 : 7002 6016 : 7002 6017: 7002 6018 : 7002 6019 : 7002 6020 : 7002 6000 : 7003 6001 : 7003 6002 : 7003 6003 : 7003 6004 : 7003 6005 : 7003 6006 : 7003 6007 : 7003 6008 : 7003 6009 : 7003 6010 : 7003 6011 : 7003 6012 : 7003 6013 : 7003 6014 : 7003 6015 : 7003 6016 : 7003 6017 : 7003 6018 : 7003 6019 : 7003 6020 : 7003 6000 : 7004 6001 : 7004 6002 : 7004 6003 : 7004 6004 : 7004 6005 : 7004 6006 : 7004 6007 : 7004 6008 : 7004 6009 : 7004 6010 : 7004 6011 : 7004 6012 : 7004 6013 : 7004 6014 : 7004 6015 : 7004 6016 : 7004 6017 : 7004 6018 : 7004 6019 : 7004 6020 : 7004 6000 : 7005 6001 : 7005 6002 : 7005 6003 : 7005 6004 : 7005 6005 : 7005 6006 : 7005 6007 : 7005 6008 : 7005 6009 : 7005 6010 : 7005 6011 : 7005 6012 : 7005 6013 : 7005 6014 : 7005 6015 : 7005 6016 : 7005 6017 : 7005 6018 : 7005 6019 : 7005 6020 : 7005 6000 : 7006 6001 : 7006 6002 : 7006 6003 : 7006 6004 : 7006 6005 : 7006 6006 : 7006 6007 : 7006 6008 : 7006 6009 : 7006 6010 : 7006 6011 : 7006 6012 : 7006 6013 : 7006 6014 : 7006 6015 : 7006 6016 : 7006 6017 : 7006 6018 : 7006 6019 : 7006 6020 : 7006 6000 : 7007 6001 : 7007 6002 : 7007 6003 : 7007 6004 : 7007 6005 : 7007 6006 : 7007 6007 : 7007 6008 : 7007 6009 : 7007 6010 : 7007 6011 : 7007 6012 : 7007 6013 : 7007 6014 : 7007 6015 : 7007 6016 : 7007 6017 : 7007 6018: 7007 6019 : 7007 6020 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6074 : 7049 6074 : 7050 6074:7051 6074 : 7052 6075 : 7046 6075 : 7047 6075 : 7048 6075 : 7049 6075 : 7050 6075 : 7051 6075 : 7052 6076 : 7046 6076 : 7047 6076 : 7048 6076 : 7049 6076 : 7050 6076 : 7051 6076 : 7052 6077 : 7046 6077 : 7047 6077 : 7048 6077 : 7049 6077 : 7050 6077 : 7051 6077 : 7052 6078 : 7046 6078 : 7047 6078 : 7048 6078 : 7049 6078 : 7050 6078 : 7051 6078 : 7052 6061 : 7053 6061 : 7054 6061 : 7055 6061 : 7056 6061 : 7057 6061 : 7058 6061 : 7059 6062 : 7053 6062 : 7054 6062 : 7055 6062 : 7056 6062 : 7057 6062 : 7058 6062 : 7059 6063 : 7053 6063 : 7054 6063 : 7055 6063 : 7056 6063 : 7057 6063 : 7058 6063 : 7059 6064 : 7053 6064 : 7054 6064 : 7055 6064 : 7056 6064 : 7057 6064 : 7058 6064 : 7059 6065 : 7053 6065 : 7054 6065 : 7055 6065 : 7056 6065 : 7057 6065 : 7058 6065 : 7059 6066 : 7053 6066 : 7054 6066 : 7055 6066 : 7056 6066 : 7057 6066 : 7058 6066 : 7059 6067 : 7053 6067 : 7054 6067 : 7055 6067 : 7056 6067 : 7057 6067 : 7058 6067 : 7059 6068 : 7053 6068 : 7054 6068 : 7055 6068 : 7056 6068 : 7057 6068 : 7058 6068 : 7059 6069 : 7053 6069 : 7054 6069 : 7055 6069 : 7056 6069 : 7057 6069 : 7058 6069 : 7059 6070 : 7053 6070 : 7054 6070 : 7055 6070 : 7056 6070 : 7057 6070 : 7058 6070 : 7059 6071 : 7053 6071 : 7054 6071 : 7055 6071 : 7056 6071 : 7057 6071 : 7058 6071 : 7059 6072 : 7053 6072 : 7054 6072 : 7055 6072 : 7056 6072 : 7057 6072 : 7058 6072 : 7059 6073 : 7053 6073 : 7054 6073 : 7055 6073 : 7056 6073 : 7057 6073 : 7058 6073 : 7059 6074 : 7053 6074 : 7054 6074 : 7055 6074 : 7056 6074 : 7057 6074 : 7058 6074 : 7059 6075 : 7053 6075 : 7054 6075 : 7055 6075 : 7056 6075 : 7057 6075 : 7058 6075 : 7059 6076 : 7053 6076 : 7054 6076 : 7055 6076 : 7056 6076 : 7057 6076 : 7058 6076 : 7059 6077 : 7053 6077 : 7054 6077 : 7055 6077 : 7056 6077 : 7057 6077 : 7058 6077 : 7059 6078 : 7053 6078 : 7054 6078 : 7055 6078 : 7056 6078 : 7057 6078 : 7058 6078 : 7059 6061 : 7060 6061 : 7061 6061 : 7062 6061 : 7063 6061 : 7064 6061 : 7065 6061 : 7066 6062 : 7060 6062 : 7061 6062 : 7062 6062 : 7063 6062 : 7064 6062 : 7065 6062 : 7066 6063 : 7060 6063 : 7061 6063 : 7062 6063 : 7063 6063 : 7064 6063 : 7065 6063 : 7066 6064 : 7060 6064 : 7061 6064 : 7062 6064 : 7063 6064 : 7064 6064 : 7065 6064 : 7066 158865.doc -130- 201217392 Χ:Υ Χ:Υ Χ:Υ Χ:Υ Χ:Υ Χ:Υ Χ:Υ 6065 : 7060 6065 : 7061 6065 : 7062 6065 : 7063 6065 : 7064 6065 : 7065 6065 : 7066 6066 : 7060 6066 : 7061 6066 : 7062 6066 : 7063 6066 : 7064 6066 : 7065 6066 : 7066 6067 : 7060 6067 : 7061 6067 : 7062 6067 : 7063 6067 : 7064 6067 : 7065 6067 : 7066 6068 : 7060 6068 : 7061 6068 : 7062 6068 : 7063 6068 : 7064 6068 : 7065 6068 : 7066 6069 : 7060 6069 : 7061 6069 : 7062 6069 : 7063 6069 : 7064 6069 : 7065 6069 : 7066 6070 : 7060 6070 : 7061 6070 : 7062 6070 : 7063 6070 : 7064 6070 : 7065 6070 : 7066 6071 : 7060 6071 : 7061 6071 : 7062 6071 : 7063 6071 : 7064 6071 : 7065 6071:7066 6072 : 7060 6072 : 7061 6072 : 7062 6072 : 7063 6072 : 7064 6072 : 7065 6072 : 7066 6073 : 7060 6073 : 7061 6073 : 7062 6073 : 7063 6073 : 7064 6073 : 7065 6073 : 7066 6074 : 7060 6074 : 7061 6074 : 7062 6074 : 7063 6074 : 7064 6074 : 7065 6074 : 7066 6075 : 7060 6075 : 7061 6075 : 7062 6075 : 7063 6075 : 7064 6075 : 7065 6075 : 7066 6076 : 7060 6076 : 7061 6076 : 7062 6076 : 7063 6076 : 7064 6076 : 7065 6076 : 7066 6077 : 7060 6077 : 7061 6077 : 7062 6077 : 7063 6077 : 7064 6077 : 7065 6077 : 7066 6078 : 7060 6078 : 7061 6078 : 7062 6078 : 7063 6078 : 7064 6078 : 7065 6078 : 7066 6061 : 7067 6061 : 7068 6061 : 7069 6061 : 7070 6061 : 7071 6061 : 7072 6061 : 7073 6062 : 7067 6062 : 7068 6062 : 7069 6062 : 7070 6062 : 7071 6062 : 7072 6062 : 7073 6063 : 7067 6063 : 7068 6063 : 7069 6063 : 7070 6063 : 7071 6063 : 7072 6063 : 7073 6064 : 7067 6064 : 7068 6064 : 7069 6064 : 7070 6064 : 7071 6064 : 7072 6064 : 7073 6065 : 7067 6065 : 7068 6065 : 7069 6065 : 7070 6065 : 7071 6065 : 7072 6065 : 7073 6066 : 7067 6066 : 7068 6066 : 7069 6066 : 7 070 6066 : 7071 6066 : 7072 6066 : 7073 6067 : 7067 6067 : 7068 6067 : 7069 6067 : 7070 6067 : 7071 6067 : 7072 6067 : 7073 6068 : 7067 6068 : 7068 6068 : 7069 6068 : 7070 6068 : 7071 6068 : 7072 6068 : 7073 6069 : 7067 6069 : 7068 6069 : 7069 6069 : 7070 6069 : 7071 6069 : 7072 6069 : 7073 6070 : 7067 6070 : 7068 6070 : 7069 6070 : 7070 6070 : 7071 6070 : 7072 6070 : 7073 6071 : 7067 6071 : 7068 6071 : 7069 6071 : 7070 6071 : 7071 6071 : 7072 6071 : 7073 6072 : 7067 6072 : 7068 6072 : 7069 6072 : 7070 6072 : 7071 6072 : 7072 6072 : 7073 6073 : 7067 6073 : 7068 6073 : 7069 6073 : 7070 6073 : 7071 6073 : 7072 6073 : 7073 6074 : 7067 6074 : 7068 6074 : 7069 6074 : 7070 6074 : 7071 6074 : 7072 6074 : 7073 6075 : 7067 6075 : 7068 6075 : 7069 6075 : 7070 6075 : 7071 6075 : 7072 6075 : 7073 6076 : 7067 6076 : 7068 6076 : 7069 6076 : 7070 6076 : 7071 6076 : 7072 6076 : 7073 6077 : 7067 6077 : 7068 6077 : 7069 6077 : 7070 6077 : 7071 6077 : 7072 6077 : 7073 6078 : 7067 6078 : 7068 6 078 : 7069 6078 : 7070 6078 : 7071 6078 : 7072 6078 : 7073 6061 : 7074 6061 : 7075 6061 : 7076 6061 : 7077 6062 : 7074 6062 : 7075 6062 : 7076 6062 : 7077 6063 : 7074 6063 : 7075 6063 : 7076 6063 : 7077 6064 : 7074 6064 : 7075 6064 : 7076 6064 : 7077 6065 : 7074 6065 : 7075 6065 : 7076 6065 : 7077 6066 : 7074 6066 : 7075 6066 : 7076 6066 : 7077 6067 : 7074 6067 : 7075 6067 : 7076 6067 : 7077 6068 : 7074 6068 : 7075 6068 : 7076 6068 : 7077 6069 : 7074 6069 : 7075 6069 : 7076 6069 : 7077 6070 : 7074 6070 : 7075 6070 : 7076 6070 : 7077 6071 : 7074 6071 : 7075 6071 : 7076 6071 : 7077 6072 : 7074 6072 : 7075 6072 : 7076 6072 : 7077 6073 : 7074 6073 : 7075 6073 : 7076 6073 : 7077 6074 : 7074 6074 : 7075 6074 : 7076 6074 : 7077 6075 : 7074 6075 : 7075 6075 : 7076 6075 : 7077 6076 : 7074 6076 : 7075 6076 : 7076 6076 : 7077 6077 : 7074 6077 : 7075 6077 : 7076 6077 : 7077 6078 : 7074 6078 : 7075 6078 : 7076 6078 : 7077 131 · 1 58865.doc 201217392 Table C: Exemplary combinations of Compound X and Compound Y Χ: Υ Υ: Υ X: YX: YX: YX: Y 6000 : 8000 6000 : 8001 6000 : 8002 6000 : 8003 6000 : 8004 6000 : 8005 6001 : 8000 6001 : 8001 6001 : 8002 6001 : 8003 6001 : 8004 6001 : 8005 6002 : 8000 6002 : 8001 6002 : 8002 6002 : 8003 6002 : 8004 6002 : 8005 6003 : 8000 6003 : 8001 6003 : 8002 6003 : 8003 6003 : 8004 6003 : 8005 6004 : 8000 6004 : 8001 6004 : 8002 6004 : 8003 6004 : 8004 6004 : 8005 6005 : 8000 6005 : 8001 6005 : 8002 6005 : 8003 6005 : 8004 6005 : 8005 6006 : 8000 6006 : 8001 6006 : 8002 6006 : 8003 6006 : 8004 6006 : 8005 6007 : 8000 6007 : 8001 6007 : 8002 6007 : 8003 6007 : 8004 6007 : 8005 6008 : 8000 6008 : 8001 6008 : 8002 6008 : 8003 6008 : 8004 6008 : 8005 6009 : 8000 6009 : 8001 6009 : 8002 6009 : 8003 6009 : 8004 6009 : 8005 6010 : 8000 6010 : 8001 6010 : 8002 6010 : 8003 6010 : 8004 6010 : 8005 6011 : 8000 6011 : 8001 6011 : 8002 6011 : 8003 6011 : 8004 6011 : 8005 6012 : 8000 6012 : 8001 60 12 : 8002 6012 : 8003 6012 : 8004 6012 : 8005 6013 : 8000 6013 : 8001 6013 : 8002 6013 : 8003 6013 : 8004 6013 : 8005 6014 : 8000 6014 : 8001 6014 : 8002 6014 : 8003 6014 : 8004 6014 : 8005 6015 : 8000 6015 : 8001 6015 : 8002 6015 : 8003 6015 : 8004 6015 : 8005 6016 : 8000 6016 : 8001 6016 : 8002 6016 : 8003 6016 : 8004 6016 : 8005 6017 : 8000 6017 : 8001 6017 : 8002 6017 : 8003 6017 : 8004 6017 : 8005 6018 : 8000 6018 : 8001 6018 : 8002 6018 : 8003 6018 : 8004 6018 : 8005 6019 : 8000 6019 : 8001 6019 : 8002 6019 : 8003 6019 : 8004 6019 : 8005 6020 : 8000 6020 : 8001 6020 : 8002 6020 : 8003 6020 : 8004 6020 : 8005 6000 : 8006 6000 : 8007 6000 : 8008 6000 : 8009 6000 : 8010 6000 : 8011 6001 : 8006 6001 : 8007 6001 : 8008 6001 : 8009 6001 : 8010 6001 : 8011 6002 : 8006 6002 : 8007 6002 : 8008 6002 : 8009 6002 : 8010 6002 : 8011 6003 : 8006 6003 : 8007 6003 : 8008 6003 : 8009 6003 : 8010 6003 : 8011 6004 : 8006 6004 : 8007 6004 : 8008 6004 : 8009 6004 : 8010 6004:8011 6005 : 8006 6005 : 8007 6005 : 8008 6005 : 8009 6005 : 8010 6005 : 8011 6006 : 8006 6006 : 8007 6006 : 8008 6006 : 8009 6006 : 8010 6006 : 8011 6007 : 8006 6007 : 8007 6007 : 8008 6007 : 8009 6007 : 8010 6007 :8011 6008 : 8006 6008 : 8007 6008 : 8008 6008 : 8009 6008 : 8010 6008 : 8011 6009 : 8006 6009 : 8007 6009 : 8008 6009 : 8009 6009 : 8010 6009 : 8011 6010 : 8006 6010 : 8007 6010 : 8008 6010 : 8009 6010 : 8010 6010 : 8011 6011 : 8006 6011 : 8007 6011 : 8008 6011 : 8009 6011 : 8010 6011 : 8011 6012 : 8006 6012 : 8007 6012 : 8008 6012 : 8009 6012 : 8010 6012 : 8011 6013 : 8006 6013 : 8007 6013 : 8008 6013 : 8009 6013 : 8010 6013 : 8011 6014 : 8006 6014 : 8007 6014 : 8008 6014 : 8009 6014 : 8010 6014 : 8011 6015 : 8006 6015 : 8007 6015 : 8008 6015 : 8009 6015 : 8010 6015 : 8011 6016 : 8006 6016 : 8007 6016 : 8008 6016 : 8009 6016 : 8010 6016 : 8011 6017 : 8006 6017 : 8007 6017 : 8008 6017 : 8009 6017 : 8010 6017 : 8011 6018 : 8006 6018 : 8007 6018 : 8008 6018 : 8009 6018 : 8010 60 18:8011 6019 : 8006 6019 : 8007 6019 : 8008 6019 : 8009 6019 : 8010 6019 : 8011 6020 : 8006 6020 : 8007 6020 : 8008 6020 : 8009 6020 : 8010 6020:8011 6000 : 8012 6021 : 8000 6021 : 8001 6021 : 8002 6021 : 8003 6021 : 8004 6001 : 8012 6022 : 8000 6022 : 8001 6022 : 8002 6022 : 8003 6022 : 8004 6002 : 8012 6023 : 8000 6023 : 8001 6023 : 8002 6023 : 8003 6023 : 8004 6003 : 8012 6024 : 8000 6024 : 8001 6024 : 8002 6024 : 8003 6024 : 8004 6004 : 8012 6025 : 8000 6025 : 8001 6025 : 8002 6025 : 8003 6025 : 8004 6005 : 8012 6026 : 8000 6026 : 8001 6026 : 8002 6026 : 8003 6026 : 8004 6006 : 8012 6027 : 8000 6027 : 8001 6027 : 8002 6027 : 8003 6027 : 8004 158865.doc •132- 201217392 X: Υ X: YX: YX: YX: YX: Y 6007 : 8012 6028 : 8000 6028 : 8001 6028 : 8002 6028 : 8003 6028 : 8004 6008 : 8012 6029 : 8000 6029 : 8001 6029 : 8002 6029 : 8003 6029 : 8004 6009 : 8012 6030 : 8000 6030 : 8001 6030 : 8002 6030 : 8003 6030 : 8004 6010:8012 6031 :8000 6031 : 8001 6031 : 8002 6031 : 8003 6031 : 8004 6011 : 8012 6032 : 8000 6032 : 8001 6032 : 8002 6032 : 8003 6032 : 8004 6012 : 8012 6033 : 8000 6033 : 8001 6033 : 8002 6033 : 8003 6033 : 8004 6013 : 8012 6034 : 8000 6034 : 8001 6034 : 8002 6034 : 8003 6034 : 8004 6014 : 8012 6035 : 8000 6035 : 8001 6035 : 8002 6035 : 8003 6035 : 8004 6015 : 8012 6036 : 8000 6036 : 8001 6036 : 8002 6036 : 8003 6036 : 8004 6016:8012 6037 : 8000 6037 : 8001 6037 : 8002 6037 : 8003 6037 : 8004 6017:8012 6038 : 8000 6038 : 8001 6038 : 8002 6038 : 8003 6038 : 8004 6018:8012 6039 : 8000 6039 : 8001 6039 : 8002 6039 : 8003 6039 : 8004 6019:8012 6020 : 8012 6040 : 8000 6040 : 8001 6040 : 8002 6040 : 8003 6040 : 8004 6021 : 8005 6021 : 8006 6021 : 8007 6021 : 8008 6021 : 8009 6021 : 8010 6022 : 8005 6022 : 8006 6022 : 8007 6022 : 8008 6022 : 8009 6022 : 8010 6023 : 8005 6023 : 8006 6023 : 8007 6023 : 8008 6023 : 8009 6023 : 8010 6024 : 8005 6024 : 8006 6024 : 8007 6024 : 8008 6024 : 8009 6024 : 8010 6025 : 8005 6025 : 8006 6025 : 800 7 6025 : 8008 6025 : 8009 6025 : 8010 6026 : 8005 6026 : 8006 6026 : 8007 6026 : 8008 6026 : 8009 6026 : 8010 6027 : 8005 6027 : 8006 6027 : 8007 6027 : 8008 6027 : 8009 6027 : 8010 6028 : 8005 6028 : 8006 6028 : 8007 6028 : 8008 6028 : 8009 6028 : 8010 6029 : 8005 6029 : 8006 6029 : 8007 6029 : 8008 6029 : 8009 6029 : 8010 6030 : 8005 6030 : 8006 6030 : 8007 6030 : 8008 6030 : 8009 6030 : 8010 6031 : 8005 6031 : 8006 6031 : 8007 6031 : 8008 6031 : 8009 6031 : 8010 6032 : 8005 6032 : 8006 6032 : 8007 6032 : 8008 6032 : 8009 6032 : 8010 6033 : 8005 6033 : 8006 6033 : 8007 6033 : 8008 6033 : 8009 6033 : 8010 6034 : 8005 6034 : 8006 6034 : 8007 6034 : 8008 6034 : 8009 6034 : 8010 6035 : 8005 6035 : 8006 6035 : 8007 6035 : 8008 6035 : 8009 6035 : 8010 6036 : 8005 6036 : 8006 6036 : 8007 6036 : 8008 6036 : 8009 6036 : 8010 6037 : 8005 6037 : 8006 6037 : 8007 6037 : 8008 6037 : 8009 6037 : 8010 6038 : 8005 6038 : 8006 6038 : 8007 6038 : 8008 6038 : 8009 6038 : 8010 6039 : 8005 6039 : 8006 6039 : 8007 6039 : 8008 6039 : 8009 6039 : 8006 6040 : 8005 6040 : 8006 6040 : 8007 6040 : 8008 6040 : 8009 6040 : 8010 6021 : 8011 6021 : 8012 6041 : 8000 6041 : 8001 6041 : 8002 6041 : 8003 6022:8011 6022 : 8012 6042 : 8000 6042 : 8001 6042 : 8002 6042 : 8003 6023 : 8011 6023 : 8012 6043 : 8000 6043 : 8001 6043 : 8002 6043 : 8003 6024:8011 6024 : 8012 6044 : 8000 6044 : 8001 6044 : 8002 6044 : 8003 6025 : 8011 6025 : 8012 6045 : 8000 6045 : 8001 6045 : 8002 6045 : 8003 6026: 8011 6026 : 8012 6046 : 8000 6046 : 8001 6046 : 8002 6046 : 8003 6027:8011 6027 : 8012 6047 : 8000 6047 : 8001 6047 : 8002 6047 : 8003 6028 : 8011 6028 : 8012 6048 : 8000 6048 : 8001 6048 : 8002 6048 : 8003 6029:8011 6029 : 8012 6049 : 8000 6049 : 8001 6049 : 8002 6049 : 8003 6030 : 8011 6030 : 8012 6050 : 8000 6050 : 8001 6050 : 8002 6050 : 8003 6031 : 8011 6031 : 8012 6051 : 8000 6051 : 8001 6051 : 8002 6051 : 8003 6032: 8011 6032 : 8012 6052 : 8000 6052 : 8001 6052 : 8002 6052 : 8003 6033:8011 6033 : 8012 6053 : 8000 6053 : 8001 6053 : 8002 6053 : 8003 6034 : 8011 6034 : 8012 6054 : 8000 6054 : 8001 6054 : 8002 6054 : 8003 6035 : 8011 6035 : 8012 6055 : 8000 6055 : 8001 6055 : 8002 6055 : 8003 6036 : 8011 6036 : 8012 6056 : 8000 6056 : 8001 6056 : 8002 6056 : 8003 158865.doc •133- 201217392 X: Υ X: Υ X: YX: YX: YX: Y 6037:8011 6037 : 8012 6057 : 8000 6057 : 8001 6057 : 8002 6057 : 8003 6038 : 8011 6038 : 8012 6058 : 8000 6058 : 8001 6058 : 8002 6058 : 8003 6039:8011 6039 : 8012 6059 : 8000 6059 : 8001 6059 : 8002 6059 : 8003 6040:8011 6040 : 8012 6060 : 8000 6060 : 8001 6060 : 8002 6060 : 8003 6041 : 8004 6041 : 8005 6041 : 8006 6041 : 8007 6041 : 8008 6041 : 8009 6042 : 8004 6042 : 8005 6042 : 8006 6042 : 8007 6042 : 8008 6042 : 8009 6043 : 8004 6043 : 8005 6043 : 8006 6043 : 8007 6043 : 8008 6043 : 8009 6044 : 8004 6044 : 8005 6044 : 8006 6044 : 8007 6044 : 8008 6044 : 8009 6045 : 8004 6045 : 8005 6045 : 8006 6045 : 8007 6045 : 8008 6045 : 8009 60 46 : 8004 6046 : 8005 6046 : 8006 6046 : 8007 6046 : 8008 6046 : 8009 6047 : 8004 6047 : 8005 6047 : 8006 6047 : 8007 6047 : 8008 6047 : 8009 6048 : 8004 6048 : 8005 6048 : 8006 6048 : 8007 6048 : 8008 6048 : 8009 6049 : 8004 6049 : 8005 6049 : 8006 6049 : 8007 6049 : 8008 6049 : 8009 6050 : 8004 6050 : 8005 6050 : 8006 6050 : 8007 6050 : 8008 6050 : 8009 6051 : 8004 6051 : 8005 6051 : 8006 6051 : 8007 6051 : 8008 6051 : 8009 6052 : 8004 6052 : 8005 6052 : 8006 6052 : 8007 6052 : 8008 6052 : 8009 6053 : 8004 6053 : 8005 6053 : 8006 6053 : 8007 6053 : 8008 6053 : 8009 6054 : 8004 6054 : 8005 6054 : 8006 6054 : 8007 6054 : 8008 6054 : 8009 6055 : 8004 6055 : 8005 6055 : 8006 6055 : 8007 6055 : 8008 6055 : 8009 6056 : 8004 6056 : 8005 6056 : 8006 6056 : 8007 6056 : 8008 6056 : 8009 6057 : 8004 6057 : 8005 6057 : 8006 6057 : 8007 6057 : 8008 6057 : 8009 6058 : 8004 6058 : 8005 6058 : 8006 6058 : 8007 6058 : 8008 6058 : 8009 6059 : 8004 6059 : 8005 6059 : 8006 6059 : 8007 6059 : 8008 6059 : 8009 6060 : 8004 6060 : 8005 6060 : 8006 6060 : 8007 6060 : 8008 6060 : 8009 6041 : 8010 6041 : 8011 6041 : 8012 6042 : 8010 6042 : 8011 6042 : 8012 6061 : 8000 6061 : 8001 6061 : 8002 6043 : 8010 6043 : 8011 6043 : 8012 6062 : 8000 6062 : 8001 6062 : 8002 6044 : 8010 6044: 8011 6044 : 8012 6063 : 8000 6063 : 8001 6063 : 8002 6045 : 8010 6045 : 8011 6045 : 8012 6064 : 8000 6064 : 8001 6064 : 8002 6046 : 8010 6046:8011 6046 : 8012 6065 : 8000 6065 : 8001 6065 : 8002 6047 : 8010 6047 : 8011 6047 : 8012 6066 : 8000 6066 : 8001 6066 : 8002 6048 : 8010 6048 : 8011 6048 : 8012 6067 : 8000 6067 : 8001 6067 : 8002 6049 : 8010 6049 : 8011 6049 : 8012 6068 : 8000 6068 : 8001 6068 : 8002 6050 : 8010 6050 : 8011 6050 : 8012 6069 : 8000 6069 : 8001 6069 : 8002 6051 : 8010 6051 : 8011 6051 : 8012 6070 : 8000 6070 : 8001 6070 : 8002 6052 : 8010 6052:8011 6052 : 8012 6071 : 8000 6071 : 8001 6071 : 8002 6053 : 8010 6053 : 8011 6053 : 8012 6072 : 8000 6072 : 8001 6072 : 8002 6 054 : 8010 6054:8011 6054 : 8012 6073 : 8000 6073 : 8001 6073 : 8002 6055 : 8010 6055 : 8011 6055 : 8012 6074 : 8000 6074 : 8001 6074 : 8002 6056 : 8010 6056 : 8011 6056 : 8012 6075 : 8000 6075 : 8001 6075 : 8002 6057 : 8010 6057:8011 6057 : 8012 6076 : 8000 6076 : 8001 6076 : 8002 6058 : 8010 6058 : 8011 6058 : 8012 6077 : 8000 6077 : 8001 6077 : 8002 6059 : 8010 6059 : 8011 6059 : 8012 6078 : 8000 6078 : 8001 6078 : 8002 6060 : 8010 6060 : 8011 6060 : 8012 6061 : 8003 6061 : 8004 6061 : 8005 6061 : 8006 6061 : 8007 6061 : 8008 6062 : 8003 6062 : 8004 6062 : 8005 6062 : 8006 6062 : 8007 6062 : 8008 6063 : 8003 6063 : 8004 6063 : 8005 6063 : 8006 6063 : 8007 6063 : 8008 6064 : 8003 6064 : 8004 6064 : 8005 6064 : 8006 6064 : 8007 6064 : 8008 6065 : 8003 6065 : 8004 6065 : 8005 6065 : 8006 6065 : 8007 6065 : 8008 6066 : 8003 6066 : 8004 6066 : 8005 6066 : 8006 6066 : 8007 6066 : 8008 15886S.doc -134- 201217392 Χ:Υ Χ:Υ X: Υ X: YX:YX: Υ 6067 : 8003 6067 : 8004 6067 : 8005 6067 : 8006 6067 : 8007 6067 : 8008 6068 : 8003 6068 : 8004 6068 : 8005 6068 : 8006 6068 : 8007 6068 : 8008 6069 : 8003 6069 : 8004 6069 : 8005 6069 : 8006 6069 : 8007 6069 : 8008 6070 : 8003 6070 : 8004 6070 : 8005 6070 : 8006 6070 : 8007 6070 : 8008 6071 : 8003 6071 : 8004 6071 : 8005 6071 : 8006 6071 : 8007 6071 : 8008 6072 : 8003 6072 : 8004 6072 : 8005 6072 : 8006 6072 : 8007 6072 : 8008 6073 : 8003 6073 : 8004 6073 : 8005 6073 : 8006 6073 : 8007 6073 : 8008 6074 : 8003 6074 : 8004 6074 : 8005 6074 : 8006 6074 : 8007 6074 : 8008 6075 : 8003 6075 : 8004 6075 : 8005 6075 : 8006 6075 : 8007 6075 : 8008 6076 : 8003 6076 : 8004 6076 : 8005 6076 : 8006 6076 : 8007 6076 : 8008 6077 : 8003 6077 : 8004 6077 : 8005 6077 : 8006 6077 : 8007 6077 : 8008 6078 : 8003 6078 : 8004 6078 : 8005 6078 : 8006 6078 : 8007 6078 : 8008 6061 : 8009 6061 : 8010 6061 : 8011 6061 : 8012 6062 : 8009 6062 : 8010 6062: 8011 6062 : 8012 6063 : 8009 6063 : 8010 6063 : 8011 6063 : 8012 606 4 : 8009 6064 : 8010 6064:8011 6064 : 8012 6065 : 8009 6065 : 8010 6065 : 8011 6065 : 8012 6066 : 8009 6066 : 8010 6066 : 8011 6066 : 8012 6067 : 8009 6067 : 8010 6067 : 8011 6067 : 8012 6068 : 8009 6068 : 8010 6068 : 8011 6068 : 8012 6069 : 8009 6069 : 8010 6069 : 8011 6069 : 8012 6070 : 8009 6070 : 8010 6070:8011 6070 : 8012 6071 : 8009 6071 : 8010 6071 : 8011 6071 : 8012 6072 : 8009 6072 : 8010 6072:8011 6072 : 8012 6073 : 8009 6073 : 8010 6073 : 8011 6073 : 8012 6074 : 8009 6074 : 8010 6074 : 8011 6074 : 8012 6075 : 8009 6075 : 8010 6075 : 8011 6075 : 8012 6076 : 8009 6076 : 8010 6076 : 8011 6076 : 8012 6077 : 8009 6077 : 8010 6077 : 8011 6077 : 8012 6078 : 8009 6078 : 8010 6078 : 8011 6078 : 8012 Table D: An exemplary combination of compound X and compound Y X: Υ X: Y Χ: Υ X: Υ 6000 : 9000 6020 : 9000 6040 : 9000 6060 : 9000 6001 : 9000 6021 : 9000 6041 : 9000 6061 : 9000 6002 : 9000 6022 : 9000 6042 : 9000 6062 : 9000 6003 : 9000 6023 : 9000 6043 : 9000 6063 : 9000 6004 : 9000 6024 : 9000 6044 : 9000 6064 : 9000 6005 : 9000 6025 : 9000 6045 : 9000 6065 : 9000 6006 : 9000 6026 : 9000 6046 : 9000 6066 : 9000 6007 : 9000 6027 : 9000 6047 : 9000 6067 : 9000 6008 : 9000 6028 : 9000 6048 : 9000 6068 : 9000 6009 : 9000 6029 : 9000 6049 : 9000 6069 : 9000 6010 : 9000 6030 : 9000 6050 : 9000 6070 : 9000 6011 : 9000 6031 : 9000 6051 : 9000 6071 : 9000 6012 : 9000 6032 : 9000 6052 : 9000 6072 : 9000 158865.doc -135- 201217392 X: Υ X: YX:YX: Υ 6013 : 9000 6033 : 9000 6053 : 9000 6073 : 9000 6014 : 9000 6034 : 9000 6054 : 9000 6074 : 9000 6015 : 9000 6035 : 9000 6055 : 9000 6075 : 9000 6016 : 9000 6036 : 9000 6056 : 9000 6076 : 9000 6017 : 9000 6037 : 9000 6057 : 9000 6077 : 9000 6018:9000 6038 : 9000 6058 : 9000 6078 : 9000 6019 : 9000 6039 : 9000 6059 : 9000 EXAMPLES Other embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims. Example 1 General Synthesis of Reagents 1 and 2

Psa3

ArOH - Acrylic Triethylamine Step 1: Synthesis of 1-Naphthyloxy Dihalothiophosphate Reagent (la)

A 500 mL round bottom flask containing a magnetic stir bar was fed with thiotrichloride (5.7 g, 33.65 mmol) and 1-naphthol (4.85 g, 33.64 mmol), and 40 mL of diethyl ether was added. The solution was cooled in a dry ice/acetone bath under an argon atmosphere. After cooling for 1 min, triethylamine (4.7 mL, 33.7 mmol), 158 865.doc - 136 - 201217392 was added and a precipitate formed. The mixture was allowed to warm to ambient temperature and then fell for 2 days. The precipitated triethylamine was filtered off and washed twice with diethyl ether. The solvent was removed under reduced pressure to give 9.8 g of Compound </ </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ·Gas thiophosphate vinegar test thank you (2α)

Add 50 mL to a 250 mL round bottom flask containing 1 naphthol-dichlorophosphorothioate reagent la (i 97 g, 7.1 mmol) and L-alanine oxime ester hydrochloride (0.99 g, 7.1 mmol) Dichloromethane. Triethylamine (1 mL' 7.2 mmol) was added under an argon atmosphere at water/ice temperature. The reaction was allowed to warm to ambient temperature and then stirred overnight. The solvent was removed using a rotary evaporator. The residue was purified by chromatography on silica gel eluting with 20% ethyl acetate. The product 2a (l. 〇 g) was obtained as a viscous oil. 31p NMR (CDC13, 64·78' 65.0) (about a mixture of diastereomers). Using the procedure described for compounds 1 a and 2a, substituting the ArOH compound listed in Table 6 for the naphthol, and replacing the L-alanine methyl chloride with the hydrochloride of the amino acid listed in Table 7 The salts were used to prepare the reagents shown in Tables 6 and 7. 158865.doc -137· 201217392 Table 6

ArOH Divaporation Reagent No. phenol/P, CI Cl lb p-fluorophenol/p~c丨Cl lc p-chlorophenol/p, ci Cl Id o-phenol phenol 'Cl c/ ci le to gas-inter-gas phenol Cl W/ ^0\,s /P, CI Cl If 158865.doc -138- 201217392

ArOH dichloride reagent number p-nonylphenol c/ Cl ig o-nonylphenol Cl lh p-methoxyphenol ^V4 Cl li & & -5 -5 -5 -5 -5 -5 -5 -5 -5 -5 l l l l l l l l 0 s ^ /4 Cl· lk 158865.doc 139- 201217392 Table 7 Amino acid aryloxy amino acid thio gas phosphate reagent No. 31pnmr (CDC13) L-alanine isopropyl ester ^VVSC1,. Person 2b 64.75 (s) 64.65 (s) L-alanine cyclohexyl ester XXVSCI human.人广2c 64.80 (s) 64.69 (s) L-alanine neopentyl ester 2d 64.59 (s) 64.31 (s) L-alanine isopropyl S is 0 0-P-Cl 2e 64.51 (s) 64.23 (s) L-alanine cyclohexyl ester C v 0 0-P-Cl 2f 64.55 (s) 64.25 (s) • 140· 158865.doc

201217392

Preparation of 2'-C-methyluridine 5'-(0-(1-naphthyl)-7V-〇S)-l-(methoxycarbonyl)ethyl)thiophosphoric acid amide (3a)

The solution of 2'-C-mercapto-protected 2'-C-mercaptopurine (262 mg, 0.8 1 mmol) in 2 mL of tetrahydrofuran was cooled in an ice/water bath under argon with 2.1 Treatment with mL tBuMgCl (l Μ, 2.1 mmol). After 10 minutes, reagent 2a (0.83 g, 2.4 mmol) was added in 2 mL of tetrahydrofuran (THF) to dissolve 158865.doc -141 - 201217392. The reaction was searched for 2 days at ambient temperature. Then, red tBuMgC1 (1 mmol) e was added for another 2 days, and the reaction was diluted with ethyl acetate and water. The organic layer was washed twice with brine and dried over sodium sulfate. The product was chromatographed using a gradient of methylene chloride containing 1 〇/〇 methanol to dichloromethane containing 1% by weight of methanol to give a G.2 g residue which was used without further purification. . To the residue was added 4 mL of an 8% aqueous solution of formic acid. The mixture was heated to 50 C using a water bath. After 2 hours, the reaction was cooled, and the solvent was removed under reduced pressure. A solution of 1.1 decyl alcohol was added to the residue. Then, it was removed under reduced pressure (4) and the addition of a 1:1 methanol:toluene solution was repeated and the solvent was removed twice. The product was isolated after chromatography using silica gel (gradient containing 4% to 8% methanol in methylene chloride). The solvent was removed and the residue was dissolved in a gas mixture and treated with an excess of hexane. The supernatant was decanted and the residual solids were left overnight by the party vacuum. Separating the product as a colorless solid) ° 31P NMR (CDC13, 67.12, 67.86) and mass spectrometry data (μ_η·, 564.5) in accordance with the desired product 3a, which is close to 1:1 for the palm of the palm In the form of a mixture of diastereomers. Example 3 Preparation of 2'-C-methyluridine 5, (0-phenyl(isopropoxycarbonyl)ethyl)thiocarbamate (3b) 158865.doc -142- 201217392

Step 1 · Compound 3b-1 - Add cyclopentanone (20 mL) and trimethyl orthoformate to a suspension of 21-mercaptopurine (2 g, 77.52 mmol) in dry CH3CN (200 mL) 20 mL), followed by the addition of p-toluenesulfonic acid monohydrate (7.4 g '38_76 mmol). The reaction mixture was stirred at 40 ° C overnight. Evaporate the solvent. The residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried <RTI ID=0.0> !H NMR (CDC13s 400 MHz) δ 8.86 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 6.06 (s, 1H), 5.73 (d, 7=8.0 Hz, 1H), 4.50 (d , /=4.8 Hz, 1H), 4.21 (m, 1H), 4.02-3.86 (m, 2H), 2.17 (m, 1H), 1.98, 1.83, 1.68 (m, 8H), 1.30 (s, 3H). Step 2: Add compound ib-methylimidazole (5 〇mL) and 2b (80 g, to a suspension of 3b-l (20 g, 61·7 mmol) in anhydrous CH3CN (100 mL). 249.2 mmol). The reaction mixture was stirred at 70 ° C for 2 hours. 158865.doc • U3· 201217392 The solvent was removed and the residue was dissolved in ethyl acetate (5 mL). The solution was washed with brine, dried and evaporated. The residue was purified by EtOAc EtOAc (EtOAc (EtOAc) 33%) &lt;&gt; 丨H NMR (cDci3, 4〇〇MHz) δ 8.79-8.92 (m, 1Η), 7.55 (m, 1H), 7.34 (m5 2H), 7.20 (m, 3H), 6.09 ( d, /=13.6 Hz, 1H), 5.70-5.61 (m, 1H), 5.06-5.01 (m, 1H), 4.38-4.09 (m, 6H), 2.08 (m, 1H), 1.96 (m, 1H) , 1.73 (m, 2H), 1.66 (m, 5H), 1.39 (m, 3H), 1.23 (m, 9H); 31P NMR (CDC13, 162 MHz) J 67.62, 67.31. Step 3: Compound 3b_ Compound 3b_2 (1 〇 g ' 16 4 mm 〇 1) was suspended in 100 mL of 80 〇 / 〇 formic acid and the reaction mixture was stirred at 50 ° C for 5 hours. The solvent was evaporated and the residue was co-evaporated with toluene to remove traces of acid and water. The residue was purified by EtOAc EtOAc (EtOAc) elute NMR (CD3OD, 400 MHz) &lt;5 7.79, 7.87 (2d, 7=8.0 Hz, 1H), 7.18-7.38 (m, 5H), 5.98, 6.01 (2s, 1H), 5.59, 5.63 (2d, 7= 8.0 Hz, 1H), 4.95-5.05 (m, 1H), 4.51-4.56 (m, 1H), 4.30-4.44 (m, 1H), 4.05-4.17 (m, 2H), 3.82-3.87 (m, 1H) , 1.34, 1.38 (2d, J=7.2 Hz, 3H), 1.17, 1.25 (2d, 7=6.0 Hz, 6H), 1.24, 125 (2s, 3H) ; 31P NMR (CD3〇D, 162 MHz) 3 68.17 , 68.40; ESI-LCMS: m/z 544.0 [M+H]+. Step 4: Separation of 3b(i)-i^ and 3b(ii)-«S&gt;-The compound 3b is separated into its preparation and diastereomer by the following two methods: (a) super Critical fluid chromatography (SFC) and (b) crystallization. 158865.doc -144- 201217392 (a) via SFC: compound 3b by SFC (for palm pak AD, 5 μιη, 25〇x3〇mm 'using 25% MeOH and 75% C〇2 as mobile phase) 440 mg' is isolated from 3b (1) and 3b (ii) in a ratio of about 1:1 to give 3b (iMP(l23.8 mg) &amp; 3b(ii)-Sp(\62.5 mg) as a white solid. 3b(i)-Rp : lH NMR (CD3OD, 400 MHz) δ 7.87 (d, J=8.4 Hz, 1H), 7.36 (t, 7=8.0 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 7.19 (t, /=7.6 Hz, 1H), 6.01 (s, 1H), 5.62 (d, /=8.0 Hz, 1H), 5.03-4.97 (m, 1H), 4.56-4.92 (m, 1H) ), 4.44-4.39 (m, 1H), 4.16-4.13 (m, 1H), 4.10-4.05 (m, 1H), 3.86 (ά^ J=9.2 Hz, 1H), 1.34 (d, J=7.2 Hz, 3H), 1.25 (d, J=6.4

Hz, 6H), 1.16 (s, 3H) ; 3IP NMR (CD3OD, 162 MHz) δ

68.18, ESI-LCMS: m/z = 544 [M+H]+. 3b(ii)-)Sp : 4 NMR (CD3〇D, 400 MHz) δ 7.89 (d, /=8.0 Hz, 1H), 7.36 (t, J=8.〇Hz, 2H), 7.30 (d, J =8.4 Hz, 2H), 7.20 (t, 7=8.0 Hz, 1H), 5.99 (s, 1H)S 5.60 (d, J=8.4 Hz, 1H), 5.03-4.97 (m, 1H), 4.56-4.51 (m, 1H), 4.35-4.30 (m, 1H), 4.14-4.10 (m, 2H), 3.83 (d, 7=9.2 Hz, 1H), 1.39 (d, J=7.2 Hz, 3H), 1.25 ( d, 7=6.4 Hz, 6H), 1.17 (s, 3H); 31P NMR (CD3〇D, 162 MHz) (5 68.42; ESI-LCMS: m/z=566 [M+Na]+. (b) By crystallization: Compound 3b (1:1, 10 g) in the form of a mixture of diastereomers was dissolved in 1 mL of dichloromethane (DCM) / diethyl ether (1:3). The alkane was allowed to stand until the solution became cloudy. The solution was left at room temperature for 5 hours and left overnight at -20 ° C. The precipitated crystals were recrystallized from DCM/diethyl ether (1:3 v/v) and again from DCM. Crystallization in /ethyl ether (1:2) to give compound 3b(1)- and 〆^ in 158865.doc • 145-201217392 pure single diastereomer. Concentrate the mother liquor after the first crystallization, and then dissolve it in In isopropyl alcohol. Second, arbitrarily burned (30% by volume). Leave clarification at room temperature Overnight liquid 'to give a small amount of crystals, which was used as seed crystals. The mother liquor was evaporated and allowed from hexane / isopropanol and crystallized twice to obtain 2.3 g 3b (ii) -Sp. Example 4

Compound 3b (85 mg, 0.156 mmol) was dissolved in 3 mL of anhydrous pyridine. Propionate gf (〇·1 mL, 0.624 mmol) was added and the mixture was left at ambient temperature for 18 hours. Water (7 mL) and ethyl acetate (7 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organic extracts were washed with water and brine, dried over Naz. The resulting oil was purified by flash chromatography using a gradient of m. m. The fractions containing the phosphorothioate were combined and concentrated in vacuo. Repurification by RP HPLC using a gradient of 50% to 100% aqueous methanol afforded 44 mg of product 4a. 31P NMR (CDCl3, 67·71, 67.74) and mass spectrometry (MH' 654.5) were consistent with the desired product 4a, which was approximately 1:1 for the diastereomeric effect of phosphorus on the 158865.doc • 146-201217392 palmar center. In the form of a mixture of bodies. Example s Preparation 2, -Deoxy-2, ♦ Gas _2, -p_C_Methyl urinary phenyl phenyl 4(7) 1 (isopropoxy oxyl) ζ * based) 琉 碟 酿 酿 酿 3 (3c)

2'-Deoxy-2'-fluoro-2.-mercaptouridine (2 mg, 〇 62 mmol) was suspended in anhydrous THF (20 mL). Add a solution of hydrazine in anhydrous THF (3 mL, 3 mmol), DMAP (4-didecylamino)

Bite) (100 mg' 0.9 mmol) and triethylamine (1 mL, 7 mmol). The reaction was stirred at 80 ° C for 18 hours. The solvent was removed, and the residue was purified mjjjjjjjjjj 4 NMR (CDC13) 3 8.49, 8.31 (m, 1H), 7.49, 7.43 (2d, *7 = 8.0 Hz, 1H), 7.31, 7.26 (m, 2H), 7.19, 7.11 (m, 3H), 6.17, 6.11 (2d, 7=7.2 Hz, 1H), 5.62, 5.53 (2d, 1H), 4.99, 4.93 (m, 1H), 4.54, 4.27 (m, 2H), 4.08, 4.02 (m, 3H), 3.89, 3.83 (m, 1H), 1.36, 1.22 (m, 6H), 1.20, 1.12 (m, 6H) ° 31P NMR (CDC13) &lt;5 68.08, 67.05. LCMS m/z 545.8 (MH+). Example 6 Preparation of 2,-deoxy-2,-α-fluoro-2,-PC-methyluridine phenyl-indole-CS)-1_(cyclohexyloxycarbonyl)ethyl)thiophosphoric acid Ester (3d) 158865.doc •147- 201217392

Compound 3d was prepared by the procedure for the preparation of compound 3c using 2c instead of 2b. NMR (DMSO-d6) δ 11.55 (s, 1H), 7.61 (d, J = 8.4 Hz, 0.43H), 7.57 (d, / = 7.6 Hz, 0.56H), 7.40 (m, 2H), 7.21. , 3H), 6.68 (m, 1H), 6·04 (m, 1H), 5.95 (d, Hz, 0.40H), 5.88 (d, J = 6.8 Hz, 0.60H), 5.57 (s, 0.50H) , 5.55 (s, 0.50H), 4.64 (s, 1H), 4.39 (m, 1H), 4.23 (m, 1H), 4.09-3.86 (m, 2H), 3.84 (m, 1H), 1.63 (s, 2H), 1.45 (s, 2H), 1.36 (brs, 1H), 1.34-1.29 (m, 11H). 31P NMR (DMSO-d6: M 67.96, 67.89; MS m/z 586.2 (MH+) 〇 Example 7 Preparation of 2'-deoxy-2,-α-fluoro-2,-p-C-methyluridine 5, _(屮Phenyl-TV-e)-1-(neopentyloxycarbonyl)ethyl)thiophosphoric acid amide (3e)

Compound 3e was prepared by substituting 2d for 2b using the procedure for the preparation of compound 3c. 'H NMR (CD3OD) δ 7.77-7, ββ (q, J = 8.0, 8.4 Hz, 1H), 7.36- 7.16 (m' 5H), 6.13 (m, 1H), 6.04 (m, 1H), 5.65- 5.56 (q, 158865.doc -148-

201217392 J=8.4} 8.0 Hz, 1H), 4.19-4.09 (m, 2H), 3.93-3.75 (m, 2H), 1.41-1.28 (m, 6H), 0.93 (s, 9H) » 31p NMR (CD3〇 D) &lt;5 66.9, 66.9. MS w/z 574.2 (MH+). Example 8 Preparation of 2'-C-methyluridine phenyl (neopentyloxycarbonyl) ethyl) thiophosphoric acid urate (3f)

2'-C-decyluridine (77 mg, 0.3 mmol) was dissolved in 1 mL of anhydrous acetonitrile and 2 mL of iV-methylimidazole. Compound 2d (0.3 g, 0.9 mmol) was added and the mixture was heated at 70 ° C for 2 h. The solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (3 mL EtOAc)EtOAc. The crude product was purified by EtOAc EtOAc (EtOAc) RP HPLC purification (gradient from 10 〇 / 〇 to 950 / 〇 methanol) was carried out on a Synergy 4μ Hydro-RP column (Phenominex) to give an analytical sample as a colorless solid. 1H NMR (CDC13): δ 9.90 (bs, 1H), 7.62-7.58 (m, 1H), 7.32-7.28 (m, 2H), 7.20-7.16 (m, 2H), 5.97 and 5.94 (2s, 1H), 5.65 and 5-52 (2d, 1H), 4.54-4.46 (m, 1H), 4.39-4.24 (m, 1H), 4.20-4.04 (m, 3H), 3.85-3.79 (m, 1H), 3.73-3.65 (m, 2H), 1.39-1.32 158865.doc • 149-201217392 (dd, 3H), 1.16-1.14 (d, 1H), 0.87-0.86 (m, 9H); 31P NMR: δ 67.85, 67.16 (1: 1 mixture of diastereomers; eSI-LCMS: m/z 570.4 [M+H] + ° Example 9 Preparation of 2'-C-methyluridine 5,-(〇-phenyl-;V_(s )-l_(cyclohexyloxycarbonyl)ethyl)thiophosphoric acid amide (3g)

Using the procedure for the preparation of compound 3f, compound 3g was prepared by substituting 2c for 2d. !H NMR (CDC13): δ 9.40 (bs, 1Η), 7.60-7.55 (m, 1Η), 7.29-7.ll (m, 5H), 5.95 and 5.92 (2s, 1H), 5.63 and 5.53 (2d, 1H), 4.75-4.68 (m, 1H), 4.50-4.23 (m, 2H), 4.10-4.00 (m, 3H), 3.74-3.72 (m, 1H), 1.80-1.05 (m, 17H); 31P NMR : &lt;5 67.80, 67.16 (3:4 mixture of diastereomers); ESI-LCMS: m/z 582.5 [M+H]+. Example 10 Preparation of 2'-C-methyluridine 5'-(0-(1-naphthylisopropoxycarbonyl)ethyl)thiophosphonium decyl ester (3h) 158865.doc •150· 201217392

Compound 3h was prepared using 2e instead of 2d using the procedure for the preparation of compound 3f. !H NMR (CDC13): δ 9.10 (bs, 1Η), 8.05-7.20 (m, 9Η), 5-95 &amp; 5.92 (23,111), 5.38 and 5.33 (2 (1,111), 4.99-4.91 ( 111, 1H), 4.59-4.28 (m, 2H), 4.20-4.03 (m, 3H), 3.72-3.69 (m, 1H), 1.36-1.27 (2d, 3H), 1.20-1.11 (m, 6H), </ RTI> <RTIgt; '-C-methyluridine 5·-(〇-(1-naphthylcyclohexyloxycarbonyl)ethyl) thiophosphoric acid amide (3i)

Using the procedure for the preparation of compound 3f, compound 3i was prepared by substituting 2f for 2d. !H NMR (CDCI3): δ 9.80 (bs, 1Η), 8.05-7.30 (m, 9H), 5.92 and 5.91 (2s, 1H), 5.38-5.29 (2d, 1H), 4.79-4.69 (m, 1H) , δ δ δ δ δ δ 158865.doc -151 - 201217392 67.74,67.43 (1:1 mixture of diastereomers); ESI-LCMS: m/z 632.5 [M+H]+ 〇 Example 12 Preparation of 2'-C-methyluridine 5'-(0-(1-Naphthylpivalyloxycarbonyl)ethyl)thiophosphoric acid urate (3j)

Using the procedure for the preparation of compound 3f, 2g was used instead of 2d to prepare the compound!H NMR (CDC13): δ 9.80 (bs, 1H), 8.05-7.30 (m, 9H), 5.90 and 5.87 (2s, 1H), 5.38 and 5.30 ( 2d,1H), 4.60-3.60 (m,9H), 3.72-3.69 (m,1H),1.41 and 1.39 (2d,3H),1.08 and 1.06 (2s, 3H),0·87 and 0.86 (2s,9H) &lt;31&gt;P NMR: d 68.01, 67.35 (1:1 mixture of diastereomers); ESI-LCMS: m/z 620.8 [M+H]+. Example 13 Preparation of S'-dimercapto 2, cardiomethyluridine 5, _(〇_phenyl_#_($) small (isopropoxycarbonyl)ethyl) thiophthalate (31 ) 158865.doc -152· 201217392

Step l: Compound 3ΐ-ι- to rc-methyluridine (2.50 g, 7 6 mm 〇1) in acetone (100 mL) in a suspension of mono-p-toluenesulfonic acid (176 g, 9.2 Methyl) and 2,2-dimethoxypropane (2 〇 mL). The mixture was stirred at room temperature for 16 hours. Saturated NaHC03 was then added to adjust the pH to about 6-7. The suspension was concentrated and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Step 2. Compound 31-2- to a solution of 31-1 (2.30 g, 7.7 mmol) in anhydrous DCM (50 mL) was added dichromic acid 0 to ingot (pdc) (5.80 g, 15·4 mmol) Then, acetic anhydride (7.87 g, 77.18 mmol) and third butanol (11.40 g, 154.0 mmol) were added. The resulting solution was stirred at room temperature for 3 hours. The mixture was loaded onto a very short cartridge column and dissolved with E A . The fractions containing 31-2 were combined and concentrated. Chromatography (EA/hexane (丨: i to 3:2)) gave 31-2 (2.07 g, 73%) as a white foam. Step 3: Compound 31-3- NaBD4 (1.10 g, 26.22 mmol) was added to a solution of 31-2 (2.07 g, 6.9 mmol) at room temperature, and the mixture was stirred overnight at 80 °C. The reaction was quenched with acetic acid (AcOH) at 〇 °C. The mixture was diluted with EA and washed with brine. The organic phase was dried and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Step 4: Compound 31-4- Compound 31-3 (850 mg, 2.8 mmol) was dissolved in 95% trifluoroacetic acid (TFA) / 5% water at 0 ° C and then stirred at room temperature for 30 min. The solvent was evaporated and the residue was purified EtOAcjjjjjjjj NMR (CD3OD, 400 MHz) δ 8.16 (d, 1Η), 5.98 (s, 1H), 5.69 (d, 1H), 3.86-3.92 (m, 2H), 1.13 (s, 3H) ; ESI-MS: m /z 261.1 [M+H]+. Step 5: Compound 31 - To a suspension of 31-4 (150 mg, 0.57 mmol) in dry EtOAc (1.0 mL) EtOAc (EtOAc) 1 M CH3CN solution). The resulting solution was stirred at room temperature for 24 hours. The mixture was diluted with hydrazine and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) 4 NMR (CD3OD, 400 MHz) δ 7.79, 7.87 (2d, 7=8.0 Hz, 1H), 7.20-7.38 (m, 5H), 5.98, 6.01 (2s, 1H), 5.59, 5.62 (2d, /=8.0 Hz, 1H), 4.99-5.01(m, 1H), 4.10-4.12 (m, 2H), 3.82-3.84 (m,lH), 1.34, 1.38 (2d, J=1.2 Hz, 3H), 1.24, 1.25( 2s, 3H), 1.17, 1.26 (2d, J=6.0 Hz, 6H); 31P NMR (CD3〇D, 162 MHz) &lt;5 68.42, 68.21 ; ESI-LCMS: m/z 546.1 [M+H]+ . Example 14 Preparation of 3'-0-acetamido-5'-dithiolated 2'-C-methyluridine 5'-(0-phenyl-W-0^)-1-(isopropoxycarbonyl) Ethyl) thiophosphoric acid amide (4d) • 154· 158865.doc

201217392

Acetic anhydride (704 mg '6.9 mmol) was added to a suspension of 31 (750 mg' 1.3 8 mmol) in anhydrous EtOAc (50 mL). The reaction mixture was heated at 35 ° C for 16 hours. The reaction was quenched with water and the solvent was removed. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 4 NMR (CD3OD, 400 MHz) &lt;5 7.78, 7.84 (2d, 7=8.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.17-7.38 (m, 5H), 5.99, 6.02 (2s, 1H ), 5.59, 5.61 (2d, 7=8.0 Hz, 1H), 5.13, 5.17 (2d, 7=9.2 Hz, 1H), 5.04-4.97 (m, 1H), 4.52-4.25 (m, 3H), 4.14- </ RTI> <RTIgt; ESI-LCMS: m/z = 585.9 [M+H]+. Example 15 Preparation of 2'-C-methylthymidine 5'-(α·phenyl-indole-5)-1-(isopropoxycarbonyl)ethyl)thiophosphoric acid amide (3 m)

158865.doc •155· 201217392 Step 1 ··Compound 3m-2· Addition of Λτ,α-bis(trimethyldecyl) to a suspension of thymidine (0.869 g, 5.63 mmol) in acetonitrile (27 mL) Acetamide (5 mL), and the mixture was refluxed for 2 hr. The solution was cooled to ambient temperature and a solution of 3 m-1 (2.0 g, 3.45 mmol) in acetonitrile (1 mL) was added. Then SnCl4 (1.6 mL '13.6 mmol) was slowly added and the reaction mixture was heated to 100 ° C for 5 hours. The reaction mixture was cooled to hydrazine.固体 Add solid NaHC〇3 and add the minimum amount of ice to the mixture. A portion of the concentrated reaction mixture was diluted with EA and treated with cold saturated aqueous NaHC03. The salt was filtered through celite and extracted with EA. The organic phase was washed successively with aq. aq. NaH.sub.3 and brine, dried over anhydrous Na? The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc: Step 2: Compound 3m-3- Compound 3m-2 (1.6 g, 2.74 mmol) / EtOAc EtOAc (EtOAc) The mixture was allowed to stand at room temperature for 20 hours. The solution was evaporated to dryness and purified residue purified eluted eluted eluted eluted ' 83.1%). NMR (MeOD, 400 MHz) ^ 8.05 (Sj 1H), 5.93 (s, 1H), 4.01-3.97 (m, 1H), 3.91-3.86 (m, 2H), 3.80 to 3.76 (m, lH), 1.85 ( s, 3H), 1.13 (s, 3H). Step 3: Add #•methylimidazole (〇4 mL) to a suspension of the compound 3m々3m_3 (15 mg, 〇55 mmol) in anhydrous CH3CN (3 mL), then add anhydrous CH3CN (1 mL) 2b (530 mg, 1.65 mmol). The resulting solution was stirred at room temperature for 12 hours. The reaction was quenched with water and the solvent was removed. The residue was purified by EtOAc (EtOAc EtOAc EtOAc EtOAc EtOAc Mg, 14.0%). 4 NMR (MeOD, 400 MHz) &lt;5 7.54, 7.64 (2s, 1H), 7.16~7.36 (m, 5H), 5.98, 6.01 (2s, lH). 5.02~4_94(m,lH), 4.56-4.52 (m, 1H), 4.43-4.29 (m, 1H), 4.17-4.02 (m, 2H), 3.94-3.84 (m, 1H), 1.81, 1.84 (2s, 3H), 1.31, 1.36 (2d, J= 7.2 Hz, 3H), 1.25-1.23 (m, 6H), 1.15 (s, 3H); 3,P NMR (MeOD, 162MHz) δ 69.17, 68.68 ; ESI-LCMS: m/z=558.1 [M+H] +. Example 16 Preparation of 1-(2-Amino-6-cyclopropylaminopurin-9-yl)-2-C-f-D-D-ribofuranosylphenyl-ΛΓ-〇5)-1-(isopropyl Oxycarbonyl)ethyl)thiophosphoric acid amide (3ζ)

KIU

3ζ·3

Step 1 · Compound 3ζ-1- at a temperature of 0 ° C to compound 3m-1 (20.0 g, 34.47 mmol) and 6-aminyl hydrazine (59 〇g, 3m mm 〇 1) in anhydrous MeCN (300 To the solution in mL) was added diazonium dicyclohexa-7-ene (DBU) (15.8 g '103.9 mmol). Here. (: The mixture was stirred for 5 minutes 158865.doc • 157·201217392 hrs, and then trimethyl sulfonyl alkyl trifluoro decane sulfonate (TMSOTf) (27.0 mL, 137.8 mmol) was added dropwise. Stirring was continued for a further 3 minutes. The mixture was then heated to 70 t: and stirred for 18 hours. The reaction was then cooled to room temperature and diluted with EA. The solution was washed with saturated NaHC 3 and brine. The organic layer was dried over NkSO4 and then concentrated. Purification of the residue (2% _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 25.6%). 丨H NMR (DMSO, d6, 400 MHz) ".38 (s, 1H), 7.97 -8.05 (m, 4H), 7.82-7.85 (m, 2H), 7.58-7.66 (m, 3H) , 7.39-7.53 (m, 4H), 7.18-7.37 (m, 2H), 7.19 (brs, 2H), 6.61 (s, 1H), 5.94 (d, X8 Hz, 1H), 4.70-4.89 (m, 3H) ), 1.58 (s, 3H). Step 2. Preparation of compound 3Z 2 - Compound guanidine, 0.16 mmol) and THF (10 mL) were placed in a dry flask and then cyclopropylamine·61 g, 28.21 mmol). After the addition, the mixture was heated to reflux overnight. The solvent was removed and the residue was purified EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Compound 3z-2 (402 mg, 0.62 mmol) &gt; glutathione in a methanol-methanol bath (2 mL, sat. sat.) and the mixture was stirred at room temperature for 12 hours. The residue was purified with EtOAc EtOAc EtOAc EtOAc (td. 5.93 (s, 1H), 4.22 (d, /=8.4 Ηζ,ΙΗ), 4.03 ^=10.8 Hz, 2H), 3.86 (d, /, = 12.8 Hz, J2=3.2 Hz, 1H), 158865.doc • 158- 201217392 2.91 (s, 1H), 0.79-0.98 (m, 2H), 0.61-0.70 (m, 2H) ; ESI-LCMS: m/z 337.1 [M+H]+, 360.1 [M+Na]+ . Step 4. Compound 3z - Add decyl imidazole (0.5 mL) to a stirred suspension of 3z_3 (ii 〇mg, 0.33 mmol) in dry acetonitrile (1 · 〇mL) at room temperature, then slowly add 2b ( l. 〇 5 g, 3.273 mmol, 1 Μ MeCN solution). The resulting solution was stirred at 50 ° C for 4 hours and then diluted with hydrazine. The solution was washed with 10% AcOH/H20, brine, 5% aqueous NaHC.sub.3, and dried over Na2SO. The solvent was removed and the residue was purified EtOAcjjjjjjjjjjj 4 NMR (CD3OD, 400 MHz) δ 7.96, 8.00 (2s, 1H), 7.28-7.36 (m, 5H), 7.14-7.20 (m, 1H), 5.96, 5.99 (2s, 1H), 4.92-4.98 (m , 1H), 4.37-4.57 (m, 2H), 4.04-4.23 (m, 3H), 2.91 (br, 1H), 1.36, 1.32 (2d, 7=7.2 Hz, 3H), 1.17-1.23 (m, 7H ), 0.96, 0.99 (2s, 3H), 0.87-0.90 (m, 2H), 0.63-0.69 (m, 2H); 3,P NMR (CD3OD, 162 MHz) 5 68.53, 68.38 ; ESI-LCMS: m/ z 622.2 [M+H]+, 644.2 [M+Na]+. Example 17 Preparation of 1-(2,6-diaminopurin-9-yl)-2-C-f-different furan ribose δα-phenyl-iV-OShl·(isopropoxycarbonyl)ethyl) thiophosphorus Glutamine (3aa)

158865.doc -159- 201217392 Step 1: Compound 3aa-1 - Compound 3z-1 (1.01 g, 1.56 mmol) was suspended in aqueous ammonia (28%, 40 mL) and dioxane (4 mL) in a sealed vessel. . The mixture was heated at 100 ° C overnight. The solvent was then removed and the residue was purified <RTI ID=0.0></RTI> to </RTI> <RTI ID=0.0></RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; 4 NMR (CD3OD, 400 MHz) δ 8.17 (s, 1Η), 5.93 (s, 1H), 4.24 (d, 7=8.8 Hz, 1H), 4.01-4.04 (m, 2H), 3.86 (dd, J; = 12.8 Hz, 72 = 3.2 Hz, 1H), 0.96 (s, 3H); ESI-LCMS: m/z 297.1 [M+H]+. Step 2: Compound 3aa-A/--mercaptoimidazole (0.5 mL) was added to a stirred suspension of 3aa-1 (62 mg, 0.20 mmol) in dry EtOAc (1.0 mL). 2b (652 mg, 2.02 mmol, 1 M MeCN solution) was added. The resulting solution was stirred at room temperature for 24 hours. The solution was diluted with EA and washed with aq. 10% aq. EtOAc, brine, 5% NaH. The solvent was removed and the residue was purified EtOAcjjjjjjjjjj NMR (DMSO-d6, 400 MHz) &lt;5 77.81, 7.83 (2s, 1H), 7.33-7.38 (m, 2H), 7.17-7.25 (m, 3H), 6.58-6.78 (m, 3H), 5.81 5.83 (m, 3H), 5.32-5.43 (m, 1H), 5.19, 5.20 (2s, 1H), 4.78-4.85 (m, 1H), 4.21-4.42 (m, 2H), 3.87-4.15 (m, 3H ), 1.24-1.26 (m, 3H), 1.08-1.15 (m, 6H), 0.83, 0.84 (2s, 3H); 31P NMR (DMSO-d6, 162 MHz) δ 68.19, 67.90; ESI-LCMS: m/ z 589.1 [M+H] +, 604.1 [M+Na]+. Example 18 15886S.doc 201217392 Preparation of 1-(2-Amino-6-allylaminopurin-9-yl)-2-C-f-different ribofuranosyl 5-(0-phenyl-#_〇5)-1 -(isopropoxycarbonyl)ethyl)thiophosphoric acid amide (3bb)

3bb-1 3bb Step 1 : Compound 3bb-1 - A mixture of 3z-1 (802 mg &lt;RTI ID=0.0&gt;&gt; The solvent was removed and the residue was purified EtOAc EtOAc EtOAc EtOAc EtOAc in. The mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4 NMR (CD3〇D, 400 MHz) δ 8.10 (s, 1Η), 5.92-6.03 (m, 2H), 5.27 (d, J=17.6 Hz, 1H), 5.14 (d, J=10.4 Hz, 1H) , 4.18-4.24 (m, 3H), 4.03 (d, J = 10.0 Hz, 2H), 3.86 (d, J = 10.4 Hz, 1H), 0.95 (s, 3H); ESI-LCMS: m/z 337.1 [ M+H]+. Step 2: Compound 3bb-Add a ruthenium-fluorenyl group 0 m (0.5 mL) to a stirred suspension of 3bb-l (200 mg, 0.59 mmol) in dry acetonitrile (1.0 mL) at room temperature, then 2b (573 mg, 1.79 mmol, 1 Μ MeCN solution) was added. The resulting solution was stirred at room temperature for 24 hours and then diluted with hydrazine. The solution was washed with a 10% aqueous solution of AcOH, brine and a 5 〇 / 〇 NaHC03 aqueous solution. The organic solution was dried and concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) 4 NMR (CD3OD, 400 MHz) δ 7.94, 7.98 (2s, 1H), 7.29-7.34 (m, 4H), 7.18-7.28 (m, 1H), 5.96-6.09 (m, 2H), 5.27, 5.31 (2s , 1H), 5.15, 5.17 (2d, /=1.2 Hz, 1H), 4.92-4.96 (m, 1H), 4.35-4.57 (m, 2H), 4.01-4.28 (m, 5H), 1.32, 1.36 (2d , 7=7.2 Hz, 3H), 1.16-1.25 (m, 6H), 0.97 (2s, 3H); 31P NMR (CD3OD, 160 MHz) δ 68.51, 68.40 ; ESI-LCMS: m/z 622.1 [M+H ]+, 644.1 [M+Na]+. Example 19 Preparation of 1-(2-Amino-6-azepin-9-yl)-2-C-rigorous-Eth-Z)-ribofuranosyl 5-(0-phenyl-too(5&gt;1-( Isopropoxycarbonyl)ethyl)thiophosphoric acid ester (3cc)

Step 1 · Compound 3cc-l- Compound 3ζ·1 (506 mg, 0.79 mmol) was dissolved in 100 mL of a methanolic solution and the mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was purified by EtOAc EtOAc (EtOAc: EtOAc (EtOAc) Add 158865.doc •162· 201217392 base 0 m嗤 (0.5 mL) to a stirred suspension of 3 cc-1 (198 mg, 0.63 mmol) in dry acetonitrile (1.0 mL) at room temperature, then add 2b (611 mg, 1.904 mmol, 1 Μ MeCN solution) The resulting solution was stirred at 30 ° C to 40 ° C for 12 hours and then diluted with EA. The solution was washed with a 1% aqueous solution of AcOH, brine and 5% NaHC. The organic phase was dried and concentrated. The residue was purified by EtOAc EtOAcjjjjjj 'H NMR (CD3OD, 400 MHz) 3 8.25, 8.28 (2s, 1H), 7.27-7.35 (m, 4H), 7.15-7.18 (m, 1H), 6.02, 6.05 (2s, 1H), 4.93-4.98 ( m, 1H), 4.40-4.54 (m, 2H), 4.20-4.27 (m, 2H), 4.05-4.13 (m, 1H), 1.15-1.35 (m, 9H), 0.99, 1.01 (2s, 3H); 31P NMR (CD3OD, 162 MHz) δ 68.66, 68.53; ESI-LCMS: m/z. Example 20 Preparation of 2'-C-uridine 5^(0-phenyl^-(5)-1-(isopropoxycarbonyl)isobutyl)thiophosphonate (3n)

To a solution of 2'-C-rigorous urea (150 mg '0.581 mmol) in MeCN (1 mL) and ΛΑ-methylimidazole (0.7 mL) was added for 2 h (651 mg, 1.86 mmol). The mixture was stirred at room temperature for 3 days. The solvent was purified and purified to purified crystals crystals crystals crystals . NMR 158865.doc -163- 201217392 (CD3OD, 400 MHz) &lt;5 7.76, 7.78 (2d, 7=9.2 Hz, 1H), 7.14-7.35 (m, 5H), 5.95, 5.97 (2s, 1H), 5.56 , 5.63 (2d, J=8.4 Hz, 1H), 4.95-5.03 (m,1H), 4.44-4.56 (m,1H), 4.30-4.41 (M, 1H), 4.08-4.11 (m, 1H), 3.75 -3.90 (m, 2H), 2.00-2.07 (m, 1H), 1.12-1.25 (m, 6H), 1.11, 1.15 (2s, 3H), 0.87-0.97 (m, 6H); 31P NMR (CD3OD, 162 MHz) δ 70.38, 69.13; ESI-LCMS: m/z 572 [M+H]+. Example 21 Preparation of 2'-C-severe uridine phenyl-; V-(S)-l-(isopropoxycarbonyl)isopentyl) thiophosphoric acid amide (3 〇)

Compound 3 was prepared using the procedure for the preparation of compound 3n &lt; *H NMR (CD3OD, 400 Μ Hz) δ 7.77, 7.84 (2d, J=8.0 Hz, 1H), 7.14-7.35 (m, 5H), 5.96 (2s, 1H), 5.57, 5.62 (2d, 7=8.0 Hz, 1H), 4.84-4.98 (m, 1H), 4.46-4.53 (m, 1H), 4.28-4.42 (m, 1H), 3.97-4.12 (m, 2H), 3.80 (2s, 1H), 1.58- </ RTI> </ RTI> </ RTI> <RTIgt; δ 68.56, 69.15 ; ESI-MS: m/z 586 [M+H]+, m/z 608 [M+Na]+. 158865.doc • 164- 201217392 Example 22 Preparation of 2,-C·methyl uridine 5,-(〇-phenyl-(tS) small (cyclohexyloxy)ethyl) thioscale (3s)

To a stirred suspension of commercially available 2'-C-decylguanosine (1 mg, 〇 34 mmol) in dry acetonitrile (1.5 mL) was added m. Sit (0.56 mL '6.8 mmol' 20 equivalents) followed by 2c (3〇3 mg, 0·84 mmol, 1 M MeCN solution). The resulting solution was stirred at 40 ° C for 3 hours and then diluted with EA. The solution was washed with a 1 〇〇 / 0 AcOH aqueous solution and brine. The organic layer was separated and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo to give a residue which was purified from EtOAc EtOAc EtOAc. The collected fractions were concentrated and purified with EtOAc EtOAc (EtOAc) 4 NMR (DMSO-d6, 400 MHz) ¢5 10.6 (s, 1H), 7.76 (d, J=5.6 Hz, 1H), 7.36-7.31 (m, 2H), 7.22-7.01 (m, 4H), 6.56 -6.48 (m, 3H), 5.74 (d, /=8.4 Hz, out), 5.42 and 5.35 (2 (1, each 1/=6.4 1^, 111), 5.16 ((1,/=2.8 1^, 1H), 4.62-3.93 (m, 6H), 1.67-1.58 (m, 5H), 1.33-1.16 (m, 12H), 0.79 (s, 3H); 3,P NMR (DMSO-d6) &lt;5 68.07 , 67.71 ; ESI-LCMS: m/z = 623.1 [M+H] + 158 865.doc - 165 · 201217392 Example 23 Preparation of C1-methylinosin 5'-(0·phenyl-^(5)-1 -(isopropoxy oxyl) ethyl) thio-chiral acid series (3 r)

Compound 3r was prepared using 2b instead of 2c using the procedure for the preparation of compound 3s. 'Η NMR (DMSO-d6, 400 MHz) δ 10.6 (s, 1H), 7.76 (d, /=1.6 Hz, 1H), 7.34-7.31 (m, 2H), 7.22-7.14 (m, 4H), 6.62 - 6.48 (m, 3H), 5.74 (d, /=7.2 Hz, 1H), 5.42 and 5.33 (2d, each 7=6.8 Hz, 1H), 5.16 (d, J=2A Hz, 1H), 4.84-3.77 (m, 1H), 4.42-3.85 (m, 5H), 1.25-1.1 (m, 12H), 0.81 and 0.8 (2s, 3H); 31P NMR (DMSO-d6) δ 68.23, 67.64 ; ESI-LCMS: m /z=583.4 [M+H]+. Example 24 Preparation of 2'-deoxy-2'-fluoroindolyl-6-methoxyguanosine phenyl-iV-(S)-l-(isopropoxycarbonyl)ethyl)-thiophosphonamide Acid ester (3t)

! 一ΝΗ V' V ΝΥΝ ΝΗ2 Using the procedure for preparing compound 3s, replacing 2c with 2b and using 2·-deoxy-2,-158865.doc -166- 201217392 fluoro-2'-C-methyl-6- Oxyguanosine replaces 2,_c_methylguanosine to prepare compound *3t〇1H NMR (DMSO-d6,400 MHz)3 7.96 &9.95 (2s, 1H), 7.36-7.29 (m, 2H), 7.21- 7.14 (m, 3H), 6.57 (br s, 2H), 6.1 and 6.05 (2d, each "/=8.8 Hz, 1H), 5.75 (br s, 2H), 4.82-4.76 (m, 1H), 4.45- </ RTI> <RTIgt; z=599.4 [M+H]+. Example 25 Preparation of 1-(2-Amino-6-methoxyindol-9-yl)-2-C-methylfuran ribose 5-(indolyl-indole-(5&gt;1-(isopropoxy) Carbonyl)ethyl)-thiophosphoric acid ester (3u)

Using the procedure for the preparation of compound 3s, replacing 2c with 2b and replacing 2'-C-methyl bird with 1-(2-amino-6-methoxyindol-9-yl)-2-C-nonylfuran ribose The glycoside was used to prepare compound 3ii. 4 NMR (DMSO-d6, 400 MHz) &lt;5 7.93 (s, 1H), 7.35-7.30 (m, 2H), 7.22-7.14 (m, 3H), 6.61-6.52 (m, 1H), 6.48 (br s, 2H), 5.86 (d, each J = 5.2 Hz, 1H), 5.43, 5.32 (br s, 1H), 5.20 (br s, 1H), 4.84-4.76 (m, 1H), 4.36-4.04 (m , 4H), 3.93 (s, 3H), 1.24-1.15 (m, 3H), 1.19-1.06 (m, 6H), 0.8-0.78 (m, 3H); 3,P NMR (DMSO-d6) &lt;5 158865.doc •167- 201217392 68.21, 67.65 ; ESI-LCMS: m/z=597.5 [M+H]+ ° Example 26 Preparation of 2'-deoxy-2'-«-fluoro-2,-/NC- 5,-(0-phenyl-N-(S)-1-(neopentyloxycarbonylethyl) thiophosphoric acid amide (3q)

Compound 3q » NMR was prepared using the procedure for the preparation of compound 3s, replacing 2c with 2d and replacing 2'-C-guanosine with 2'-deoxypurine α-fluoro-2'-y^C-methylguanosine. DMSO-d6,400 MHz), 10.66 (br s, 1H), 7.79 (s, 1H), 7.36-7.30 (m, 2H), 7.22-7.15 (m, 3H), 6.61-6.52 (m, 1H), 6.48 (br s5 2H), 6.72-6.56 (m, 3H), 6.00, 5.95 (2d, /=8.0, 8.4 Hz, 1H), 5.75-5.82 (m, 1H), 4.43-3.92 (m, 5H), 3.76-3.53 (m, 2H), 1.29.1.24 (m, 3H), 1.09-1.00 (m, 4H), 0.84, 0.81 (2s, 8H); 31P NMR (DMSO-d6) δ 68.09, 68.03; ESI- LCMS: m/z = 613.7 [M+H]+. Example 27 Preparation of 2'-C-methyladenosine 5'-(0-phenylpivalyloxycarbonyl)ethyl)thiophosphonate (3dd)

lS8865.doc -168- 201217392 Compound 3dd was prepared using the procedure for the preparation of compound 3s, replacing 2c with 2d, and replacing 2'-C-nonylguanosine with 2,_c_methyladenosine.咕Nmr (DMSO-d6, 400 MHz) &lt;5 8 22, 8.2 (2s, 1H), 8.12 (s, 1H) 7.36-7.13 (m, 6H), 6.61-6.55 (m, 1H), 5.97, 5.94 (2s, 1H) 5.40, 5.34, 5.31 (3d, 7=6.8, 6.8, 6.0 Hz, 2H), 4.39-3.99 (m, 5H), 3.76-3.61 (m, 2H), 3.42 (d, 7=10.4) Hz, 1H), 1.27-1.23 (m, 3H), 0.83, 0.77 (2s, 4H), 0.77, 0.76 (2s, 8H); 31p NMr (DMSO-d6) δ 68.15, 67.74 ; ESI-LCMS: m/ z=595.〇[M+H]+. Example 28 Preparation of 2'-C-methyladenosine 5,-(0-(1-naphthylisopropoxy)ethyl)thiophosphonate (3ee)

Compound 3dd was prepared using the procedure for the preparation of compound 3s, replacing 2c with 2e, and replacing 2'-C-nonylguanosine with 2'-C-methyladenosine. 4 NMR (DMSO-d6, 400 MHz) δ 8.28, 8.24 (2s, 1H), 8.12-8.06 (m, 2H), 7.93-7.91 (m,1H), 7.29-7.68 (m, 1H), 7.54-7.37 (m, 4H), 7.26 (br s, 2H), 6.82-6.72 (m, 1H), 6.00, 5.98 (2s, 1H), 5.47, 5.39, 5.31 (3d, "7=6.4, 6.8, 10.0 Hz, 2H), 4.82-4.74 (m, 1H), 4.48-4.35 (m, 2H), 4.28-4.15 (m, 2H), 4.03-3.96 158865.doc -169- 201217392 (m, 1H), 1.27-1.24 ( m, 3H), 1.1-1.00 (m, 6H), 0.8 (s, 3H); ESI-LCMS: m/z = 617.1 [M+H] + ° Example 29 Preparation of 2,-C-methylguanosine (•Pentyloxycarbonyl)ethyl)thiophosphonium oxime ester (3P)

Step 1: Compound 3p-1 - 2'-C-decylguanosine (1.0 g, 3.36 mmol), ruthenium citrate (20 mL) and p-toluene monohydrate (961) were stirred at room temperature. A mixture of mg, 5.05 mmol) in 1,4-dioxacarbaldehyde (30 mL) for 24 h. Dowex MWA-1 basic resin was added and stirred until the solution was neutralized. The resin was filtered, and the filtrate was concentrated with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. 3p-l (0.94 g). Step 2: Compound 3p-2- was stirred at 25 ° C with 3 p-1 (0.94 g, 2.77 mmol), dimethylamine. Specific bite (DMAP) (338 mg, 2.77 mmol) and butyltributyl chlorodecane (TBSC1) (543 mg, 3.60 mmol) in pyridine 15S865.doc •170·

The solution in 201217392 (10 mL) was overnight. Add 4-methoxytrimethane chloride (i 56 g, 5.0 mmol)' and stir the resulting mixture for 3 hrs at RT 5 (dichloroacetic acid mixture was diluted with ethyl acetate and washed three times with brine. The residue was subjected to silica gel chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc)

2.66 mmol) and 1·〇 浴Tetrabutylammonium fluoride (TBAF)/THF (4 mL) in a 1 mL mL THF bath for 20 hours. Concentrate the solution. The residue was subjected to flash chromatography (yield: 5% to 6% MeOH) to afford 1.33 g. MS m/z 611·9 (MH+). Step 3: Compound 3p - Compound 2d (1,0 M MeCN solution, 0.5 mL) was added dropwise to 3p-2 (61 mg '0.1 mm 〇i) and diisopropylethylamine (0.3 mL) in anhydrous acetonitrile In a solution (0.4 mL). At 82. (: heating the resulting solution for 20 hours 'diluted with ethyl acetate, washed three times with brine, dried over sodium sulfate and concentrated" to carry out gelatin chromatography (containing 20% to 30% ethyl acetate in hexane) to give 82 mg The white foamy protected intermediate was dissolved in a mixture of 80% formic acid and 20% water (3 mL). The solution was stood at room temperature overnight, concentrated, and then co-evaporated three times with MeOH/toluene. Chromatography (containing 6% to 10% MeOH in DCM) afforded EtOAc (yield: EtOAc (EtOAc: EtOAc) , 5.88, 5.90 (2s, 1H), 4.33-3.53 (m, 2H), 4.11- 4.24 (m, 3H), 3.61-3.79 (m, 2H), 1.39, 1.36 (2d, /=7.2 Hz, 3H) , 0.94, 0.95 (2s, 3H), 0.84, 0.87 (2s, 9H); 31P NMR (acetone-d6) d 68.27, 67.85; ESI-LCMS: w/z 611.3 [M+H]+. Example 30 158865. Doc •171- 201217392 Preparation of 2', ,5'〇S)-C,C-dimethyladenosine 5,-(phenylphenyl small (neopentyloxycarbonyl)ethyl) thiophosphoric acid amide (3hh)

2 -C-methylguanosine was used to prepare compound 3hh. Nmr (cD3〇D) j 8.40, 8.36 (2s,1H), 8.22, 8.20 (2s,1H), 7.07-7.36 (m,5H), 6.06, 6.05 (2d, 7=5 2 Hz, 1H), 5.88 , 5.90 (2s, 1H), 4.59 (t, J=5.2 Hz, 0.5 H), 4&gt;5〇(q&gt; j=5 2 Hz, 1H), 4.40 (q, /=3.6, 5.2 Hz, 0.5H ), 4.04 .4 19 (mj 2H), 3.81 (d, 7=0.8 Hz, 1H), 3.75 (d, 7=10.4 Hz, 1H), 3.65 (d, J=10.4 Hz, 1H), 1.52, 1.40 (2d, J=6.4 Hz, 3H), 1.29, 1.30 (2s, 3H), 0.93, 0.87 (2s, 9H); 31p NMR (two 蜩-d6) J 68.40,67.43 ; ESI-LCMS: w/z 595.1 [M+H]+. Example 31 Preparation of 1-(2-amino-6-methoxyindol-9-yl)-2-C-methylfuran Ribose 5-(C&gt;-phenyl-anthracene). (neopentyloxycarbonyl)ethyl)-thiophosphoric acid ester (3v)

158865.doc 201217392 The procedure for the preparation of compound 3p was used to replace 2,-C-methyl with 1-(2-amino-6-methoxy.anthracene-9-yl)-2-C-nonylfuran ribose Birds were all prepared to compound 3v. NMR (CD3OD, 400 MHz) (5 7.97, 8·〇〇 (2s, 1H) 7.10-7.33 (m, 5Η), 5.99, 5.96 (2s, 1Η), 4.33-4.55 (m, 2Η),

4.031, 4.034 (2s, 3H), 3.56-3.72 (m, 2H), 1.31-1.36 (m, 3H), 0.94, 0.92 (2s, 3H), 0.89, 0.85 (2s, 9H); 31P NMR (DMSO- D6) δ 68.52, 68.27. ESI-LCMS: m/z 625.3 [M+H] + 〇 Example 32 Preparation of 1-(2-amino-6-methoxyindole-9-yl)-2-C-methylfuro sucrose 5-( 0_phenyl-AT_(S)-l-(cyclohexyloxycarbonyl)ethyl)_thiophosphoric acid (3w)

Using the procedure for the preparation of compound 3p, replacing 2d with 2c and replacing 2'-C-methyl bird with 1-(2-amino-6-decyloxy-9-yl)-2-C-nonylfuran ribose Glycoside is used to prepare compound 3w. 4 NMR (CD3OD, 400 MHz) &lt;5 7.98, 8.01 (2s, 1H), 7.24-7.32 (m, 4H), 7.10-7.17 (m, 1H), 6.00, 5.96 (2s, 1H), 4.36-4.73 (m, 3H), 4.036, 4.034 (2s, 3H), 4.01-4.22 (m, 3H), 1.60-1.80 (m, 4H), 1.19-1.55 (m, 9H), 0.92, 0.94 (2s, 3H) 31P NMR (DMSO-d6) δ 68.43, 68.32 » ESI-LCMS: m/z 637.6 [M+H]+. 158865.doc •173· 201217392 Example 33 Preparation of 1-(2-Amino-6-methoxyindol-9-yl)-2-C-methylfuran ribose naphthyl neopentyloxycarbonyl)ethyl)_ Thiophosphonate (3x)

Using the procedure for the preparation of compound 3p, replacing 2d with 2g and replacing 1-(2-amino-6-decyloxy-9-yl)-2-C-methyljD-ribofuranose with 2--(^ The guanosine is used to prepare the compound 3. 111\]^11(匚0300,400 1^1^)&lt;5 8.15-8.19(m,lH),8.03,7.97 (2s,lH), 7.80-7.85 (m , lH), 7.31-7.67 (m, 5H)S 6.00, 5.98 (2s, 1H), 4.43-4.62 (m, 2H), 4.18-4.27 (m, 3H), 4.01 (s, 3H), 3.57-3.79 (m, 2H), 1.33-1.37 (m5 3H), 0.941, 0.946 (2s, 3H), 0.855, 0.848 (2s, 9H); 31P NMR (DMSO-d6) J 68.55, 68.57. ESI-LCMS: m/ z 675.3 [M+H]+. Example 34 Preparation of other 2'-C-methyluridine 5'-thiophosphoramidate The compound 3ii as shown in Table 8 was prepared using a similar procedure for the preparation of compound 3n. 3vv 158865.doc • 174- 201217392 Table 8 Compound 31p NMR ppm Compound 31p NMR ppm H Hd bH 3ii 69.30 69.09 Cl, Η 〇3jj 68.92 68.58 Q, Cl 0-P_0々X Speak HH “H 3kk 68.45 68.16 F\ PH 〇HH"H 311 69.69 69.28 opo^XJ^ 3mm 68.60 68.42 Q, DPO^Y into the pound Hd, 3nn 68.25 67.79 n (3-PO^X ^ speak HH "H 3oo 69.25 69.12 into. VH H"H 3pp 69.52 68.53 175- 158865.doc 201217392

Example 35 Preparation of 2'-C-methyl-3'-0-propyl uridine 5'-(0-phenylisopropoxycarbonyl)ethyl)-thiophosphoric acid urate (4b) 158865 .doc

-176-

S 201217392 Compound 3b (1 g, 1.88 mmol) was dissolved in 1 mL of anhydrous hydrazine, and propionic anhydride (385 mg ' 2.81 mmol) was added and the reaction mixture was left overnight at room temperature. TLC showed that the reaction was not completed. Additional anhydride (385 mg, 2.81 mmol) was added and the mixture was heated at 40 °C for 2 h. Evaporate the solvent. The residue - was partitioned between ethyl acetate and water. The organic layer was washed with brine <RTI ID=0.0> Chromatography by column chromatography (containing 2 ° / ◦ to 7 ° / methanol)

The gradient of DCM) was purified to give 725 mg 4b (64%). NMR (CDC13): J 8.70 and 8.66 (23,111), 7.59-7.48 (2 &lt;1,111), 7.30-7.08 (m, 5H), 5.93^5.90 (2s, 1H), 5.60iL5.49 (2d , 1H), 5.01-4.94 (m, 2H), 4.50-4.38 (m, 1H), 4.32-4.02 (m, 3H), 2.45-2.35 (m, 2H), 1.38-1.30 (m5 3H), 1.20- 1.11 (m, 12H); 31P NMR: &lt;5 67.72, 07.54 (1:1 mixture of diastereomers); Example 36 Preparation of 2',3'-i&gt;-diisobutyl-2,-C-methyluridine 5,-(ί7_phenyl 1-(isopropoxy)ethyl)thione Stearic acid ester (^... and preparation of 2'-C-mercapto-oxime-isobutyluridine 5,-(p-phenylene 1 (isopropoxy)ethyl) thiophosphoric acid Vinegar (4f) 158865.doc •177· 201217392

Step 1 : Compound 4c - Add hydrazine (22 mg, 0.18 mmol) to a solution of 3b (01 g, 〇18 mmol) in anhydrous hexane (2 mL) under N.sub.2. (〇 1 mL, 0.63 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of isopropanol (〇·5 mL). The solvent was removed under vacuum and the residue was dissolved in EA (1 mL). The solution was washed with saturated NaHC 3 and brine. The organic layer was separated, dried over anhydrous Na.sub.4 and filtered. The filtrate was concentrated in vacuo to give crystals crystals crystals crystals crystalssssssssssssssssssssssssss 1H NMR (DMSO-d6, 400 MHz) &lt;5 11.46 (s, 1H), 7.59 and 7.55 (2d, ·7=8·4, 8.4 Hz, 1H), 7.37-7.32 (m, 2H), 7.21- 7.15 (m, 3H), 6.67-6.66 (〇1,111), 6.14 and 6.11 (each single peak, 111), 5.58 ((1,&gt;/=8.0 1^,111), 5.2 (br s, 1H ), 4.88-4.84 (m, 1H), 4.28-4.27 (m, 1H), 3.95-3.85 (m, 1H), 2.54-2.49 (m, 2H), 1.38 and 1.36 (2s, 3H), 1.26-1.21 (m, 2H), 1.56-1.12 (m, 6H), 1.09-1.05 (m, 12H); 31P NMR (DMSO-d6)^ 68.44, 68.42; ESI-LCMS: m/z=682.4 [M-Η] 158865.doc .178· 201217392 Step 2: Compound 4f - Further dissolving the residue on a silica gel column with 5% MeOH in DCM. (54.5 mg). H NMR (DMSO-d6, 400 MHz) &lt;51142 (s, iH), 7.65 &amp; 7.63 (2d, J = 8.0, 8.4 Hz, lH), 7.37-7.32 (m, 2H) , 7.21-7.15 (m, 3H), 6.68-6.61 (m, 1H), 5.84 and 5.81 (each single peak, 1H), 5.71 and 5.68 (each single peak, ih), 5.56 and 5.47 (each doublet, Each &gt;/=8.〇112,111), 4.98-4.94 (111,111), 4.87-4.82 (ms 1H)&gt; 4.31-4. 16 (m, 3H), 3.85-3.95 (m, 1H), 2.62-2.58 (m, 1H), 1_26 and 1.2 (each doublet, /=7.2, 6.8 Hz, 3H), 1-16-1.08 ( Ιη, 12H), 1.01 (s, 3H); 31P NMR (DMSO-d6) δ 68.93, 67.96; ESI-LCMS: m/z=612.4 [M+H]+. Uridine 5,-(0-phenylisopropoxycarbonyl)ethyl)thiophosphonate (4e)

Step 1: Compound 4e-1 - under N2, fraction of 2'-C·methyl uranyl (2_〇g 158865.doc 179· 201217392 7.6 mmol) in ice-cold solution in anhydrous pyridine (2 mL) 1,3-Dichloro-1,1,3,3-tetraisopropyldioxane (TIPDSC12) (2.40 g, 7.6 mmol) was added in small portions. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was dissolved in EA (100 mL). The solution was washed with saturated NaHC(R)3 and brine. The organic layer was separated, dried over anhydrous Na? The filtrate was concentrated in vacuo to give crystals crystals crystals crystals crystalsssssssssssssssssssssssssssssssssss Step 2. Compound 4e-2- Add NaH (384 mg, 16 mmol) to a solution of 4e-1 (2.0 g, 4.0 mmol) in anhydrous THF (30 mL). The mixture was stirred at 0 °C for 30 minutes, after which time Ch3I (1 2 g ' 8 mmol) was added and stirring was continued for 4 hours at 〇 ° C. The mixture was diluted with EA (100 mL) and washed with saturated NaHC.sub.3 and brine. The organic layer was dried over Na 2 SO 4 and concentrated to give a residue, which was purified on silica gel column (0 匸^4/]^0^1 = 100/1 to 50/1) to give a white blister. (556 mg, 26.93%) 〇 step 3 · Compound 4e-3- to 4e-2 (556 mg, 1.08 mmol) in MeOH (10 mL). . The mixture was stirred at 80 ° C for 12 hours. The solvent was removed and the residue was purified EtOAcjjjjjjjjj NMR (DMSO-d6, 400 MHz) δ 11.39 (brs, 1H), 8.07 (d, 7 = 8.0 Hz, 1H), 5.91 (Sj 1H), 5.63 (d, 7=8.0 Hz, 1H), 5.21 (t , /=4.8 Hz, 1H), 5.05 (d, 7=8.0 Hz, 1H), 3.78-3.82 (m, 2H), 3.59-3.71 (m, 2H), 158865.doc •180· 201217392 3.36 (3, 3H), 1.08 (s, 3H); ESI-LCMS: m/z=273.1 [M+H]+. Step 4·Compound 4e - To a stirred suspension of 4e-3 (170 mg, 0·63 mmol) in dry THF (2 mL) was added decyl imidazole (0 5 mL) followed by 2b (598 mg) , 1.875 mmol). Stir at 70 ° C • The reaction mixture was allowed to stand for 1 hour. The solvent was evaporated and the residue was purified EtOAcjjjjjjjjjjj 4 NMR (CD3OD, 400 MHz) δ 7.77, 7.85 (2d, J=8.0 Hz, 1H), 7.18-7.36 (m, 5H), 6.09, 6.12 (2s, 1H), 5.54, 5.63 (2d, J=8.0 Hz, 1H), 4.94-5.01 (m, 1H), 4.49-4.53 (m, 1H), 4.26-4.39 (m, 1H), 4.03-4.13 (m, 2H), 3.77-3.81 (m, 1H), 3.47 (s, 3H), 1.32, 1.36 (2d, 7=7.2 Hz, 3H), 1.18-1.24 (m, 6H); 31P NMR (CD3OD, 162 MHz) δ 68.2, 67.7 ; ESI-MS: m/z 558.2 [M+H]+. Example 38 The structures of Compounds 3a to 3vv and 4a to 4f are shown in Table 9. 158865.doc • 181 · 201217392 Table 9 Compound Product 31pnmr (solvent) MS / y) s 〇丫丫 0 if h/ %h 3a 67.12 67.86 (CDC13) 564.5 (M-H') s .丫K 丫. Human VhH 3b 67.16 67.71 (CDCI3) 543.2 (MH*) C( S °γΚγ° Λγ&quot;ΤΡΝ^ 3c 67.05 68.08 (CDCI3) 545.8 (Mlf) OS °γΚγ° 3d 67.89 67.96 (DMSO) 586.2 (MH^ 158865.doc •182· 201217392 Compound product 31pnmr (solvent) MS ^ S. 丫R 丫 3e 66.9 66.9 (CD3OD) 574.2 (ΜΗ&quot;) Q 丫y 0 〇-P-〇^V/°v&gt;N^ ^Λνη ηΗ 3f 67.85 67.16 570.4 (MH^ ^ ° 丫口丫. 〇ιχτ°Λ^:Ν^ 1 Η(? %Η 3g 67.80 67.16 582.5 (MH+) φ yr λ^°ύ^ν^ 1 HC? ^)Η 3h 67.92 67.28 592.2 ο丫口丫〇CXXX0^0 i HC? 3i 67.74 67.43 632.5 158865.doc 183 · 201217392 The product product 31pnmr (solvent) MS. Y has &gt;r〇xim ,rx^ 3j 68.01 67.35 620.8 (MH) qsy丫γ λΧ'Ι0 η1 &quot; i HO ΟΗ 31 68.42 68.21 546.1 Q 丫γ 〇〇—ρ— Τ HO ΟΗ 3m 69.17 68.68 558.1 (MH+) Q,..丫V. Person::^ by i HO *OH 3n 70.38 69.13 572 (MKT) Q , ry everyone, H )-4^ i HO ^OH 3o 69.15 68.56 586 (MH+) 158865.doc -184- 201217392 Compound product 31pnmr (solvent) MS Qs C 0 〇-P-〇^V/°N&gt;&gt;r〇xcm hR (λ N NH2 3p 68.27 67.85 611.3 (MI^) 0 qs ^〇4-〇^〇Y^^2 &gt;γ〇λτη H 3q 68.09 68.03 613.7 (MH^ 0 Q f &lt;;ϊλνη ΛΧ1η°Λ^ 2 1 H(? %H 3r 68.23 67.64 583.4 (MH^ 0 Q s &lt;NVSr cxXt°^N NH2 i HO OH 3s 68.07 67.71 623.1 ( ΜΗΓ) Q, 0 person wi HO ^ och3 ά N NH2 3t 68.21 67.82 599.4 (MH, 158865.doc -185- 201217392 Compound product 31pnmr (solvent) MS och3 Qs &lt;NxbL λχ1η°Τ^ν n NH2 I Hcf OH 3u 68.21 67.65 597.5 (MR&quot;) OCH3 Qs &lt;nyS ^OPO-^V/O^ N NH2 ^T〇xrNH h〇H 3v 68.52 68.27 625.3 (MH+) 〇ch3 Q, &lt;nyS N NH2 i H(? OH 3w 68.43 68.32 637.6 (MH+) __v OCH3 jo-po^V/〇s&gt;NN nh2 yu i HO OH 3x 68.55 68.57 675.3 (MH&quot;) α); ί〇^Ν 1 3y 68.66 68.36 687.4 (MH^ 158865.doc -186 - 201217392 Compound product 31pnmr (solvent) MS A HN Q s &lt;: Χλνη Λο^0ΛΥ Ϊ H(? %H 3z 68.53 68.38 622.2 (Mrf) nh2 Qs &lt;Nxbl ΛΧΧ°Λ^Ν N NH2 3aa 68.19 67.90 589.1 (MIT) NH Q s &lt;;ϊλ, λ〇4χ〇Ύ^ 2 3bb 68 .51 68.40 622.1 (MR&quot;) Q ^ ΛΧΧ°Λ^ 1 HC? OH 3cc 68.66 68.53 601.1 (MH, nh2 Q t &lt;;ϊ&gt; ο 〇-ρ-〇Ά/°\/ &gt;Ρ〇\ΝΗ 1 1 HO OH 3dd 68.15 67.74 595.0 (MH, 158865.doc -187- 201217392 Compound product 31P NMR (solvent) MS ^ &lt;: ϊ3 i HO OH 3ee 68.49 67.46 617.1 (MlT) s 〇rv° 3ff 67.78 66.86 569.4 ( Ml)· CX? s 〇ry° 3gg 68.11 67.06 597.5 (Ml)' %〇VrN^NH2 Ο NH c 二\\ / HO OH 3hh 68.40 67.43 595.1 (MH^ 0-P_0々X ^ Speak H Hd bH 3ii 69.30 69.09 562.2 (MH, u. Opo^^X speak HH "H 3jj 68.92 68.58 578.0 (M^) 158865.doc -188- 201217392 Compound product 31pnmr (solvent) MS Q, V/J〇 speak HH "H 3kk 68.45 68.16 578.1 (MH+) F\ / Ci Η n says h “H 311 69.69 69.28 618.0 (M+Na)+ speak HH “H 3mm 68.60 68.42 558.0 (MR1) Ri〇^0 Π 1 '-1-*·^. V H"H 3nn 68.25 67.79 558.2 (MH+) H 〇 O-P-O^X. Speak H H"H 3oo 69.25 69.12 574.0 (MH^ m.^° to H H"H 3pp 69.52 68.53 595.0 (MH&quot;) 158865.doc -189- 201217392

Compound product 31pnmr (solvent) MS Q , OPO^X ^ speak HH "H 3qq 70.03 69.56 545.1 (MH+) Q, 3rr 68.87 68.76 626.2 (M+Na)+ Q,&quot;分. λρ^Η 3ss 70.83 69.38 530.0 ( M^) Q 异〜.力. Human 乂Hd bH 3tt 69.12 68.45 558.0 _+) Q, 〇°l7° opo^^ ^ y〇^Hd bH 3uu 69.14 68.46 572.0 (VfflO 158865.doc 190-

201217392 Compound Product 3Ipnmr (solvent) MS λ 〇 3w 68.74 66.82 620.0 (MH+) S .丫K 丫. Person!; — I / 7 x 4a 67.71 67.74 (CDC13) 654.5 (M-H·) Q .丫 Y people win. . 1" 4b 67.72 67.54 598.3 (MH+) ^ 〇丫g 丫. x0^^crJ ο 4c 68.44 68.42 682.4 (MH+) 158865.doc -191 - 201217392 Compound product 31pnmr (solvent) MS s DD °h0〇H 4d 68.90 68.23 585.9 (MH^^°γΝγ〇人1 HC? %CH3 4e 68.2 67.7 558.2 (MH+) 〇5^νη ^ 4f 68.93 67.96 612.4 Example 39 General nucleoside 5'-0-(l-thiotriphosphate) Synthesis 158865.doc 192- 201217392 nCnh + α-Γα s

R = 〇H or F hydrogen pyrophosphate (tetrabutylammonium)

The 1,2,4-triazole (42 mg, 0.6 mmol) was suspended in 1 mL of dry CH3CN. Triethylamine (0.088 mL, 0. 63 mmol) was added and the mixture was vortexed to give a clear solution. After addition of PSC13 (0.01 mL, 0.1 mmol), the mixture was vortexed and left for 20 minutes. The mixture was then centrifuged. The supernatant was added to the nucleoside (0.05 mmol) and the mixture was kept at ambient temperature for 1 hour. Add hydrogen pyrophosphate (tetrabutylammonium) (180 mg, 0.2 mmol). The mixture was then kept at room temperature for 2 hours. The reaction was cooled in an ice water bath and quenched with water. Separation of 5^3 in the form of a mixture of diastereomers by IE chromatography on a AKTA detector (AKTA Explorer) using a column HiLoad 16/10 with Q Sepharose High Performance Phosphate ester. Separation was performed using a linear gradient of 0 158 865.doc -193 - 201217392 N to 1 N NaCl in 50 mM TRIS buffer (pH 7.5). The fractions containing the nucleotide ... thiotriphosphate were combined, concentrated and desalted by RP HPLC on the same column as in the column of Example 3. A linear gradient of 50 mM triethylammonium buffer containing 〇% to %% methanol was used for dissolution over 2 Torr at a flow rate of 1 〇 ml/min. Two separate compounds corresponding to individual diastereomers for the phosphorus to palm center are collected. Analytical RP HPLS was performed on a Synergy 4 micron Hydro-RP column (Phenominex) in 50 mM triethylammonium acetate buffer (pH 7.5) containing 〇% to 25% linear gradient of acetonitrile over 7 minutes. The residence time (RT) of individual diastereomers is provided in Table 10> Table 10·α-thiotrisate structure 3iPNMR Pa 3, pnmr pp 3, P NMR Ργ MS R_T. 分锉0 Γ) s Γ ΧΝΗ HO-fOS-ο-Ι-ο-, 〇in iH Ah γγ. 0 HO OH 5b 43.17 d 21.69 m -5.32 d 513.0 4.17 HO DH 5a 42.89 d -21.75 q -5.28 d 513.0 4.50 h/\ Sc 43.14 d -23.80 m -10.20 bs 515.0 4.90 158865.doc -194- 201217392 Structure 31pnmr Pa 3,pnmr pp 31p NMR Ργ MS RT minutes ηο&quot;Ηηο1γ'υ^° j~K 5d 42.12 d -23.48 q -6.49 d 515.0 5.52 θά c!)h oh &lt;!&gt;hj~~ 5e 43.42 d -21.93 q -5.47 d 554.3 5.39 d)H OH d)H ^~~ 5f 43.07 d 21.90 q -5.40 d 554.2 5.79 c0c hos_4〇jwY ^^2 OH OH OH )- H〇i)H 5g 43.41 d -23.26 m -10.10 bs 552.2 5.23 &lt;ySt OH OH 〇H \- H〇〇H 5h 43.12 d -24.20 m -11.05 d 552.2 5.82 RT = The residence time is shown in Table 10. Sa and 5b are diastereomers and can be distinguished by the palmarity of the cardiac phosphorothioate. Similarly, 51) and 5c; % and 5e; and 5h are diastereomeric oxime, respectively, and can be distinguished by the palmarity of α-phosphorothioate. 158865.doc •195· 201217392 Example 40 HCV replicon assay cells containing 2 mM L-glutamic acid supplemented with 10% heat-inactivated fetal bovine serum (FBS), 1% penicillin-bondomycin (penicillin-streptomyocin Self-replicating subgenomic HCV containing a stable luciferase (LUC) reporter gene in 1% non-essential amino acid and 0.5 mg/ml G418 in Dulbecco's modified Eagle's medium (DMEM) Replicon of Huh-7 cells. Determination of anti-HCV activity The 50% inhibitory concentration (EC5Q) of the compound against HCV replicon cells was determined by the following procedure. On the first day, 5,000 HCV replicon cells per well were seeded in 96-well plates. On the next day, the test compound was dissolved at 100 ° /. The final test concentration required for 1 DMSO in DMSO. Each compound was then serially diluted (1:3) to 9 different concentrations. 100% DMSO containing the compound was reduced to 10% DMSO by 1:10 dilution in cell culture medium. The compound was diluted to 10% DMSO with cell culture medium and used to administer HCV replicon cells in a 96-well format. The final DMSO concentration was 1%. HCV replicon cells were incubated at 37 ° C for 72 hours. At 72 hours, cells were treated while the cells were still subconfluent. Compounds that reduce the LUC signal were identified by Bright-Glo Luciferase Assay (Promega, Madison, WI). The percent inhibition at each compound concentration was determined relative to control cells (untreated HCV replicons) to calculate the EC50. The compounds of formula (I) are active in replicon assays. Exemplary compounds 158865.doc -196-201217392 Antiviral activity is shown in Table 11, where "A" indicates EC50 &lt; 1 μΜ, "Β" indicates EC5〇 &lt;10 μΜ, and "C" indicates EC5〇&lt; 100 μΜ. Table 11

Compound ECs〇 Compound ECs〇 Cp Ϊ ηο 5η A S ΟγΝ^Ο B Human 〇 HO OH A {^ 异 Ογ^γΟ cx. level. A ^ s °yy° 〇 〇-ρ-〇Ά/°\&gt;Ν^ &gt;r〇ArNH A .丫 Η 丫.丫, 人τνη Η- 1 纛 HO OH A i °γΒγ° ClXX0^ft: N^ t Hi OH A C^s .丫 K 丫. Hi? ^)H A 158865.doc -197- 201217392

Compound EC5〇 Compound EC50.丫 u 丫. 〇L〇r:r^:N^ i HC? ^)H A.丫 y Π—〇zV^〇s^&gt;N,^ &gt;^〇\ΝΗ Η- 1 1 HO OH A i .丫 Λ〇 Π;°Λ^Ν ^ 1 HO ΟΗ A 1 ΟγΝγΟ ^rT? A V&quot;.丫 ; π; \^^ I HO OH A Q .丫 y λ^&quot;°Τ?ν^ i HO OH C i . For the sake of people: ^:. 1 Η o' OH B 0 Q t &lt;;Χλ, 0 0—P—N nh2 &gt;γ°^ hR A ^o-|-o^V^〇s^NN &&gt;γΛνη h〇HA 0 Q &lt;NVSr N NH2 AOQ 3 &lt;NVSr (Χχΐ:°Ύ^ N NHi i HO OH A OCH3 Q f &lt;;XX human level. 1 N NH2 A 158865.doc •198- 201217392

Compound ECs〇 compound ECs〇PCHj Q s &lt;χλ N NH! A och3 Q, 〇&amp; ^opo^y〇sVN N nh2 &gt;r〇x^mh〇HA QCH3 A 识0&amp; ^o-|-o *^V^〇s&gt;NN NHz A 〇^1.1 person 2 X HO1 OH A Qs &lt;Nxi Λ^τ°Ύ^Ν n NHj A nh2 Qs &lt;nyS Λ^τ°Λ^:ν N NH2 A NH Q t &lt;:Χλνη ΛΧΓΛ^: t HC? %WA Qs &lt;ntV Λ^ίΓΛίξ: N NH2 A nh2 Q s A ,-. NH, o Λ0^Χ°Λ^ A CX, s 〇rv0 ^ Vmvr C 158865.doc -199- 201217392

Compound ECs〇 compound ECs〇cf\ Η n opo^^^T^ Speak HH “HA Η Η Η”Η AQ, 〇0l7° Cl OPO^^^T^ Speak HH “HAF\ /Cl Η 〇^ sn〇lNJ OP-O'^X Hd bH A opo^^^ y\ speak HH "HAQ, y^\ Hd· bH A , 〇\ Η n 03 〇〇l7 speak H Hd bH A cP4〇^° ho bH AQ, . °i7° opa^C^ speak HH “HAQ s &quot;°β° X,bH BQ, ^〇;*° B -200- 158865.doc 201217392

Compound ECs〇 Compound ECs〇 Q.~. ° force. Hd bH A 〇ο-ρ-ο^Χ y〇H^Hd bH AQ, opo^XV 1,NH HC5' bH λ0 BQ i &lt;nyV 1 ?0_卜0—1 Y eight N eight NH2 people 々H fried CH3 OH OH A OMe fL·^ &lt;iA, OH OH A OMe Q ^ &lt;yS I 〇OPO-] Y eight N eight NH2 person y float CH3 OH FA CX〇s α 〇&quot;° person V you CS.丫R 丫. A | 〇丫*^丫. People are flat. i'ΐΗ A | 丫. People are flat. A 158865.doc 201 - 201217392 Compound ECso compound ECs〇 S D D VH A O s 〇 i^y·0 v^〇^q: Vnh \/NH &lt; ~. A Example 41 NS5B inhibition assay The enzyme activity of NS5B570-Con 1 (δ-21) was measured as the amount of bismuth telluride in the acid-insoluble RNA product. A complementary IRES (cIRES) RNA sequence was used as a template corresponding to 377 nucleotides from the 3' end of the HCV(-) strand of RNA from the Con-prion strain, with a base content of 21% Ade, 23% Ura, 28% Cyt and 28% Gua. The cIRES RNA was transcribed in vitro using the T7 transcriptome (Ambion, Inc.) and purified using the Qiagen RNeasy maxi kit. The HCV polymerase reaction contained 50 nM NS5B570-Conl, 50 nM cIRES RNA, approximately 0.5 μM 氚 ΝΤΡ, 1 μΜ competitive cryopreservation, 20 mM NaCl, 40 mM Tris-HCl (pH 8·〇), 4 mM dithiothreitol, and 4 mM MgCl 2 . At 3 7. (: Next, the standard reagent was incubated for 2 hours in the presence of increasing concentrations of inhibitor. At the end of the reaction 'RNA was precipitated with TCA and the acid-insoluble RNA product was filtered through a size exclusion 96-well culture dish. Thereafter, scintillation fluid was added and the radiolabeled RNA product was detected using a Trilux Topcount scintillation counter according to standard procedures. Compound concentration was calculated by fitting the data to a nonlinear regression (S-curve) to calculate a 50% reduction in enzyme catalysis rate ( IC5〇). IC5G values were obtained from the average of multiple independent experiments 158865.doc • 202·201217392 and are shown in Table 12. Compounds of formula (I) exhibit activity in this assay. The value of “A” in the table below indicates IC50&lt;; 1 μΜ, the value of “B” indicates IC5〇&lt;10 μΜ, and the value of “C” indicates the value of IC5〇&lt;100 μΜ. Table 12

Structure ICS0 Value 5a &quot;? Α 〇\Ν, /ΝΗ OH OH ΟΗ \ Ύ \ / \ HO ΟΗ C 5b 0 0 S \ ΝΗ OH OH OH Τ Ύ \ / \ ΗΟ ΟΗ A 5c 0 0 S \ ΝΗ H0- P-0-[3-0-p-0^\/0\//N'^J OH OH ΟΗ \ Ύ $ / ·\ HO FB 158865.doc 203 - 201217392

Structure ICS0 value 5d 〆Ο 0 S \ /NH H〇-|='-〇-P-〇-P-〇^\/0\&gt;N'^/ OH OH OH \ / 〇/ \ HO F c 5e ^=N ho-popopo \ γ \ OH OH OH ) HO F nh2 A 5f ^=N ho-popopo \ γ \ OH OH OH J ^ HO F nh2 A 5g ^=N ho-popopo \ γ \ OH OH OH i ~~ HO OH nh2 A 5h ^=N ho-popopo \ γ \ OH OH OH j ^ HO OH nh2 B Example 42 Hepatocyte activation assay • 204· 158865.doc 201217392 The inoculated human liver cell line was purchased from CellzDirect. A DMSO solution of 30 μM of 5 mM test article (Compound 3a) was administered to a medium (3 mL) containing about 1.5 million human hepatocytes in each well to achieve a final concentration of 50 μM. After incubation at 37 ° C for 6 hours, the medium was removed and the cells were washed twice with 500 μM cold 0.9% NaCl aqueous solution. An aliquot of 500 μM cold methanol/Η20 (70/30) was added to the wells to dissolve the hepatocytes. The cells were scraped from the wells and the entire contents were transferred to a microcentrifuge tube (Eppendorf tube). After storage at -20 ° C for more than 3 hours, the lysate was allowed to warm to room temperature, vortexed and centrifuged. The supernatant was evaporated in a Speed-Vac and the sample was reconstituted with 500 pL of 1 mM aqueous ammonium hydroxide solution. 20 pL was injected into the LC/MS/MS system to specifically detect the alpha-thiotriphosphate of the test article (see Figure 1, face D). HPLC separation was achieved using a Thermo HyPurity C18 column (5 〇 x 2.1 mm, 3 μ particle size). The mobile phase consisted of 3 mM ammonium formate and 10 mM aqueous dimethylhexylamine solution, and mobile phase B consisted of 3 mM ammonium formate and 10 mM decyl hexylamine in acetonitrile/H20 (50/50). HPLC elution was carried out via a linear gradient of increasing mobile phase B at a flow rate of 0.22 ml/min. Compounds 5a and 5b were detected by anionic MRM mode by Sciex API 3200. In Fig. 1, the faces A, B, C and D show the following. A面A: HPLC chromatogram of a synthetic sample of α-thiotrilinic acid S 5a in 300 mM aqueous solution of ammonium citrate. BB: HPLC chromatogram of a synthetic sample of α-thiotriphosphate 5b in an aqueous solution of 3 00 nM in 1 mM. Panel C: HPLC chromatogram of a specially prepared 1:1 mixture of 150 nM of a synthetic sample of α-thiotriphosphate diastereomers 5a and 5b in 1 mM aqueous ammonium phosphate solution. This display distinguishes between compounds 5a and 5b. D面D: lies in 158865.doc • 205· 201217392 HPLC chromatogram of the α-thiotriphosphate diastereomer formed after incubation of compound 3a in human hepatocytes. As illustrated by face D, only compound 5b was formed. Example 43 Compound combination assays were tested using the HCV genotype lb HCV replicon with the stable luciferase (LUC) reporter gene in Huh7 cells. Species or more than two test compounds. Under standard conditions, Duss modified Igers containing 10% heat-inactivated fetal bovine serum (FBS; Mediatech Inc, Herndon, VA), 2 mM L-face lysine and non-essential amino acids (JRH Biosciences) The cells were cultured in medium (DMEM; Mediatech Inc, Herndon, VA). HCV replicon cells were seeded in 96-well culture dishes at a density of 104 cells per well in DMEM containing 10% FBS. On the next day, DMEM containing no compound (as a control), DMEM containing test compounds serially diluted in the presence of 2% FBS and 0.5% DMSO, or serial dilution in the presence of 2% FBS and 0.5% DMSO The medium was replaced with DMEM of compound 3b in combination with one or more test compounds. The cells were incubated for 72 hours in the absence of the compound (as a control), in the presence of the test compound, or in the presence of a combination of compounds. The direct effect of the combination of compounds was tested using a luciferase (LUC) based reporter gene assay as determined by the Bright-Glo Luciferase Assay (Promega, Madison, WI). A dose-response curve for the combination of two or more test compounds of individual compounds and fixation ratios is determined. 158865.doc •206– 201217392 The effects of test compound combinations are evaluated by two separate methods. In the Loewe additivity model, by using

CalcuSyn (Biosoft, Ferguson, MO) (a computer program based on the method of Chou and Talalay) analyzes experimental replicated subdata. The program uses experimental data to calculate the combination index (CI) values for each of the experimental combinations tested. A CI value &lt;1 indicates a synergistic effect, a CI value of 1 indicates an additive effect, and a CI value &gt; 1 indicates an antagonistic effect. The second method for evaluating the combination uses a program called Macsynergy π. The MacSynergy II software is courtesy of Dr. M. Prichard (University of Michigan). The Prichard model (Prichard M〇del) allows for a three-dimensional study of drug interactions and calculates the synergistic capacity produced by replicon assays using a disc combination of two or more inhibitors (synergy v〇lume) ) (Unit: μΜ 2%). The synergistic capacity (forward capacity) or the antagonistic capacity (negative capacity) indicates the relative amount of synergy or antagonism at each change in the concentration of the two drugs. Collaborative capacity and antagonistic capacity are defined based on the Bliss independence model. In this model, a synergistic capacity of less than -25 indicates an antagonistic interaction, a capacity in the range of _25 to 25 indicates an additive effect, and a capacity in the range of ι 〇〇 is not synergistic and capacity &gt;1〇〇 Then indicates a strong synergy. In vitro exostatic, synergistic, and strong synergistic effects of assay compound combinations can be used to predict the therapeutic benefit of administering a combination of compounds in vivo to an infected patient. The combined ci and synergistic capacity results are provided in Table 13. 158865.doc -207- 201217392 Table 13 Cl Synergistic Capacity of Combination Compounds at EC50 (μΜ2°/«) INX-189 0.42 65 PSI-938 0.73 27 PSI-6130 0.78 15 PSI-7851 1.1 0 GS-9190 0.92 79 Filibuvir 0.85 23 ANA-598 0.02 161 7008 0.01 127 VX-222 0.67 38 VX-950 0.06 76 ITMN-191 0.28 126 TMC-435 0.5 126 BMS-790052 0.64 26 Virus. Sitting 1 22 pegylated interferon 0.33 117 complex interferon 1 31 cyclosporin A 0.07 60 BILN-2061 0.7 31 HCV-796 0.42 31 IFN-λΙ 0.35 116 IFN42 0.49 34 ΙΡΝ-λ3 0.63 35 In addition, While the above is a more detailed description of the embodiments of the present invention, it will be understood that Therefore, it is to be understood that the invention is not to be construed as limited to the scope of the invention BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates four chromatograms labeled A, B, C, and D from the results of a hepatocyte activation assay. Figure 2 shows an exemplary HCV protease inhibitor. Figure 3 shows an exemplary nucleoside HCV polymerase inhibitor. 158865.doc •208-

201217392 Figure 4 shows an exemplary non-nucleoside HCV polymerase inhibitor. Figure 5 shows an exemplary NS5A inhibitor. Figure 6 shows exemplary other antiviral agents. Figures 7A-7I show exemplary compounds of formula (I). Figures 8A-8I show exemplary compounds of formula (AA) and their tri-acids. Figures 9A-9B show exemplary compounds of formula (BB). Figure 10 shows the formula (DD). 158865.doc -209-

Claims (1)

201217392 VII. Scope of application: 1. A compound of formula (1) or a pharmaceutically acceptable salt thereof R6 R7 wherein: B1 is optionally substituted heterocyclic base or optionally substituted heterocyclic base having a protected amine group; R1 is selected from the group consisting of 〇·, 〇Η, as appropriate Substituted hydrazine-linked amino acid and optionally substituted hydrazine-substituted oleic acid vinegar derivative; R2 is selected from the group consisting of: an optionally substituted aryl group, as appropriate, taken from a heterocyclic group substituted as appropriate and r21o-p-OR20 o-P-OR19, wherein R, R20 and R21 are independently absent or are murine ' and η is 0 or 1; the restriction is when R1 is 〇 -or 0, R2 is R21〇-i-〇-p-OR2. Ar19 R3a&amp;R3b is independently selected from the group consisting of hydrogen, deuterium, optionally substituted C丨6 alkyl, optionally substituted C26 alkenyl, optionally substituted C2·6 alkynyl, Substituted CN6 haloalkyl and aryl (Cw alkyl); or together with an optionally substituted C36 cycloalkyl; 158865.doc 201217392, r4 selected from the group consisting of τ: hydrogen, azide Substituted, optionally substituted c!·6 alkyl group, optionally substituted c2 6 alkenyl and optionally substituted C2.6 block; R5 is selected from the group consisting of hydrogen, halogen, azide Base, cyano group, optionally substituted C!_6 alkyl group, -〇R10 and -0C(=0)R&quot;; K6 is selected from the group consisting of chlorine, a hydroxyl group, a gas group, an atmosphere group, Substituted CN6 alkyl, 〇R12 and _〇c(= 〇)R13; R7 is selected from the group consisting of hydrogen, halogen, azide, cyano, optionally substituted C1-6 Alkyl, 〇R14 and _〇C(= 〇)R15; or both R and R are oxygen atoms and are bonded together by a carbonyl group; R8 is selected from the group consisting of argon, halogen, azide , cyano group, optionally substituted CN6 alkyl group, _〇r16 and _〇c(= 〇)R17; R9 is selected from the group consisting of hydrogen, azide group, cyano group, optionally substituted CN6 Alkyl and -OR!8; R 〇, R12, R14, R16 and R18 are independently selected from the group consisting of hydrogen and optionally substituted Cu alkyl; and R11, R13, R15 and R17 are independently Substituted Ci-6 alkyl and optionally substituted C3.6 cycloalkyl; with the proviso that when R3a, R3b 'R4, R7, uldent 8 and r9 are all hydrogen, 'R6 is not azide base. 2. A compound of claim 1 wherein R8 is optionally substituted C16 alkyl. 3. The compound of claim 2, wherein R8 is fluorenyl. 4. The compound of claim 1, wherein R8 is halogen. -2· 158865.doc 201217392 5. The compound of claim 1, wherein Rs is hydrogen. 6. For the compound of item 1 or 2, the aryl group is replaced by the 目 我 ^ ^ γ κ 马 马 马 。 。. 7. The compound of claim 6 wherein the optionally substituted aryl group is an optionally substituted phenyl group. 8. The compound of claim 6, wherein the optionally substituted aryl group is an optionally substituted naphthyl group. 9. The compound of claim 1 or 2, wherein R2 is optionally substituted heteroaryl 0. 10. The compound of claim 1 wherein R2 is r21〇-αο-ρ-OR15; η is Π is OR20 1 And R, R19, R2. And r" is independently 〇- or 〇Η 11. The compound of claim 1 or 2, wherein r2 is r21〇-P-〇-p OR19 0 ; and R1, R2, and R2丨 are independently 〇- Or OH ο 12. The compound of claim 1 or 2 wherein R is an optionally substituted a-amino acid. 13. The compound of claim 1 or 2 wherein Ri is optionally substituted A compound of claim 1 or 2, wherein R1 is selected from the group consisting of alanine, aspartic acid, aspartic acid, cysteine Aminic acid, face acid, glutamic acid, glycine, lysine, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, A Thiamine, albinoic acid, threonine, tryptophan, valine and their esters are derived 158865.doc 201217392. 15. 16. 17. 18. 19. 20. 21. The compound of claim 14 Wherein R1 is selected from the group consisting of: isopropyl propylate, cyclohexyl propylamine, neopentyl alamate, isopropyl citrate, and isopropyl methinate. The compound of claim 15 wherein R1 is Isopropyl amide R22〇Rf R24 The compound of claim 1 or 2 wherein r1 has the structure Ο HN—^ wherein R is selected from the group consisting of hydrogen, optionally substituted C!-6 alkane a C3.6 cycloalkyl group, optionally substituted aryl, optionally substituted aryl (Cu Hyun "base" and optionally substituted t-alkyl; R23 is selected from the group consisting of Group: hydrogen, optionally substituted indol-6 alkyl, optionally substituted Cie haloalkyl, optionally substituted Gw cycloalkyl, optionally substituted qaryl, optionally substituted Further, an aryl group and optionally substituted aryl group (Ci. 6 alkyl group); and r24 is hydrogen or optionally substituted C 4 alkyl group; or a caliper 23 together with R 24 forms an optionally substituted C 3 . The compound of claim 17, wherein R23 is an optionally substituted alkyl group. The compound of claim 18, wherein the optionally substituted C.6 alkyl group is a decyl group, an ethyl group, a positive group. a propyl, isopropyl, n-butyl, isobutyl or tert-butyl group. Wherein the substituted alkyl group is methyl beta, such as the compound of claim 18, wherein the optionally substituted CM yun 158865.doc 201217392 is substituted with one or more substituents selected from the group consisting of: Amine amino, mercapto, alkylthio, optionally substituted aryl, hydroxy, optionally substituted heteroaryl, c-carboxy and amine. 22. A compound of claim 7 wherein R24 is hydrogen 23. The compound of claim 17, wherein R24 is optionally substituted μ. ^ 1 -6 base. 24. The compound 'mr22' of claim 7 is an optionally substituted ~ alkyl group. A = compound of claim 7 wherein r22 is an optionally substituted &amp; The compound of claim 1 or 2, wherein at least one of R3a and at least one is substituted iCl.6 alkyl; and the other of R3a&amp;R3b is hydrogen. The compound of the month long term 28] wherein the optionally substituted c i ·6 alkyl group is a mercapto group. Α 3〇. The compound of claim 1 or 2, wherein R4 is hydrogen. 31. The compound of claim 1 or 2, wherein R4 is azido. 32. A compound according to claim, wherein R4 is optionally substituted Cw alkyl. 33. The compound of claim 1 or 2, wherein R5 is hydrogen. 34. The compound of claim 1 or 2, wherein R6 is hydrogen. 35. The compound of claim 1 or 2 wherein the rule 6 is _〇Ri2. 36. The compound of claim 35, wherein R12 is hydrogen. 37. The compound of claim 35, wherein Ri2 is an optionally substituted a 6 alkyl group. 38. The compound of claim 1 or 2, wherein R6 is _〇c(=〇)Ri3. 39. The compound of claim 1 or 2, wherein _〇Ri4. 40. The compound of claim 39, wherein R14 is hydrogen. 41. The compound of claim 39, wherein R!4 is an optionally substituted Ci 6 alkyl group. π 42. A compound according to item 1 or 2, wherein R7 is _〇C(=〇)r15. 43. The compound of claim 1 or 2 wherein R7 is a halogen. 44. The compound of claim 1 or 2, wherein R6 and R7 are both oxygen atoms and are joined together by a plurality of groups. 45. The compound of claim 1 or 2, wherein R9 is hydrogen. 158865.doc -6 - 201217392 The compound of claim 1 or 2 wherein Βι is selected from the group consisting of 46. wherein: RA2 is selected from the group consisting of hydrogen, halogen, and nhrJ2, wherein R" is selected from the group consisting of hydrogen, -C(= 〇)rk2, and -C(=0)0RL2; RB2 is Halogen or NHRW2, wherein Rw2 is selected from the group consisting of hydrogen, optionally substituted Cw alkyl, optionally substituted C2.6 alkenyl, optionally substituted C38 cycloalkyl, _c(=〇 RM2 and -C(=0)ORN2; RC2 is hydrogen or NHR(1), wherein R〇2 is selected from the group consisting of hydrogen, -C(=〇)RP2, and _c(=〇)〇RQ2; RD2 The group consisting of hydrogen, dentate, optionally substituted base, optionally substituted core and optionally substituted c2_6 alkynyl; R is selected from the group consisting of nitrogen and Substituted cw alkyl, optionally substituted C3 8 cycloalkyl, _c(=〇)rR2 and 158865.doc 201217392 -C(=〇)〇RS2 ; RF2 is selected from the group consisting of hydrogen, Halogen, optionally substituted C..6 alkyl, optionally substituted C2.6 alkenyl, and optionally substituted C2.6 fast radical; Y2 is N or CR12, wherein RI2 is selected from the group consisting of Group: hydrogen, ii, optionally substituted C 6 alkyl, optionally substituted C 2 · 6 dilute and optionally substituted c 2 -6 c radical; RG 2 is optionally substituted C m alkyl; RH 2 is hydrogen Or NHRT2, wherein Rn is independently selected from the group consisting of: hydrogen, -C(=0)RU2, and _c(=〇)〇rV2, and RK2, rL2 'rM2, rN2, rP2, rQ2, rR2, rS2 , rU2 and R 2 are independently selected from the group consisting of 6 alkyl, ^"alkenyl, c2.6 alkynyl, C3.6 cycloalkyl, c3 6 cycloalkenyl, c3 6 cycloalkynyl, C6 -1 () aryl, heteroaryl, heteroalicyclic, aryl (C16 alkyl), heteroaryl (Cw alkyl) and heteroalicyclic (Cl. 6 alkyl). 47. The compound of claim 46. 48. The compound of claim 46. 49. The compound of claim 46 158865.doc 201217392 NH The compound of claim 46, wherein the compound of claim 1 is a compound of claim 1, wherein the compound of formula (1) is selected from the group consisting of OH F OH ΟΗ ΝΗ〇 I58865.doc -9- 201217392 158865.doc -10- 201217392 158865.doc -11 - 201217392 ο 158865.doc -12- 201217392 158865.doc -13- 201217392 158865.doc 201217392 ο ο-ρ-σ ΝΗ HO ΟΗ Η ο ο ο-ρ-σ ΝΗ HO ΟΗ Ό Η η ΗΟ ΟΗ Η Q ο-ρ-σ ΝΗ ΗΟ ΟΗ Η C Η (5 ΟΗ or its pharmaceutically acceptable salt 〇 ο-ρ-ο ΝΗ 53. The compound of claim 1, wherein the compound of formula (I) is hydrazine or a pharmaceutically acceptable salt thereof Q f &lt; Νχ ^ ^op-〇-^V/〇s &gt; NN nh2 &gt;r〇 ArNH hH- 54. The compound of claim 1, wherein the compound of formula (I) is W 〇 H0 &quot;F or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound of formula (I) is Ο or its pharmaceutically acceptable salt (ΝΗ人. HO OH 158865.doc -15- 201217392 Wherein the compound of formula (i) is or a pharmaceutically acceptable salt thereof. 57. If requested! A compound wherein the compound of the formula (1) is selected from the group consisting of: 58. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to π, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient Or a combination thereof. The use of a compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 58, for the manufacture of a medicament for ameliorating or treating a viral infection. 60. The use of claim 59, wherein the viral infection is caused by a virus selected from the group consisting of: adenovirus, alphaphaviridae, worm, arbovirus, astrovirus (Astr〇) Virus), Bentoviridae J5Sm.doc 201217392 (Bunyaviridae), Coronaviridae, Filoviridae, Flaviviridae, Hepadnaviridae, Vivoviral ( Herpesviridae), Alphaherpesvirinae, Betaherpesvirinae, Gammaherpesvirinae, Norwalk Virus, Astroviridae, Cup Caliciviridae, Orthomyxoviridae, Paramyxoviridae, Paramyxovirus, Rubulavirus, Morbillivirus, Lactovirus (Papovaviridae), the small DNA virus family (Parvoviridae), the small RNA virus family (Picornaviridae), the foot and mouth disease virus family (Aphthoviridae) , Cardioviridae, Enteroviridae, Coxsackie virus, Polio Virus, Rhinoviridae, Phycodnaviridae, Pox Department of Virology (Poxviridae), Reoviridae, Rotavirus, Retroviridae, Retrovirus, Immunodeficiency Virus, Pombacterium Virus, Avian Sarcoma Virus, arbovirus (Rhabdovirus), Rubiviridae, and Togaviridae 51 (51. A compound of any one of claims 1 to 57 or a pharmaceutically acceptable compound thereof The use of a salt or a pharmaceutical composition according to claim 58 for the manufacture of a medicament for ameliorating or treating an HCV infection.] 58865.doc -17 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The use of a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting the activity of NS5B polymerase. 63. Use of a compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting viral replication. Use of a compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for contacting a virus-infected cell for improving or treating the viral infection. 65. The use of claim 62, 63 or 64, wherein the medicament improves or treats an HCV viral infection. 66. Use of a compound according to any one of claims 1 to 57, or a pharmaceutical composition as claimed, for the preparation of a medicament for ameliorating or treating a viral infection wherein the medicament is manufactured with one or more A combination of agents selected from the group consisting of interferon, ribavirin, protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound; compound of formula (AA), which is mono-acidic And a second acid vinegar or triphosphate; a compound of the formula (BB), and a compound of the formula (DD), or a pharmaceutically acceptable salt of any of the above compounds. 67. The use of claim 66, wherein the one or more agents are selected from the group consisting of: compounds 1001 to 1014, 2001 to 2010, 3001 to 3008, 4001 to 4005, 5001 to 5002, 7000 to 7077, 8000 to 8012 and 9000, or a pharmaceutically acceptable salt of any of the above compounds. 68. The use of claim 66 or 67, wherein the medicament improves or treats HCV disease 158865.doc • 18 · 201217392 infection. 69. Use of a compound according to any one of claims 1 to 57 for the manufacture of a medicament for contact with a virus-infected cell, wherein the medicament is manufactured with one or more selected from the group consisting of Combination of agents: interferon, ribavirin, HCV protease inhibitor, HCV polymerase inhibitor, NS5A inhibitor, antiviral compound; compound of formula (AA), its monophosphate, diphosphate or triphosphate; (BB) a compound, and a compound of formula (DD), or a pharmaceutically acceptable salt of any of the above. 70. The use of claim 69, wherein the one or more agents are selected from the group consisting of: compounds 1001 to 1014, 2001 to 2010, 3001 to 3008, 4001 to 4005 '5001 to 5002, 7000 to 7077 '8000 to 8012 and 9000, or a pharmaceutically acceptable salt of any of the above compounds. 71. The use of claim 69 or 70, wherein the medicament ameliorates or treats an HCV infection. 158865.doc -19-